Treatment with alpha 7-selective ligands

ABSTRACT

The present invention includes methods, uses, and selective α7 nAChR agonist compounds for treating or preventing metabolic disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims benefit to U.S. Provisional ApplicationSer. Nos. 60/971,654, filed Sep. 12, 2007; 60/953,610, filed Aug. 2,2007; 60/953,613, filed Aug. 2, 2007; and 60/953,614 filed Aug. 2, 2007,each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention includes methods, uses, and selective α7 nAChRagonist compounds for treating or preventing metabolic disorders.

BACKGROUND

Many patients who have insulin resistance or Type 2 diabetes mellitus(T2DM) often have several symptoms that together are referred to assyndrome X, or metabolic syndrome. Metabolic syndrome is a combinationof medical disorders that increase the risk for cardiovascular diseaseand diabetes. Metabolic syndrome affects as much as 25% of the USpopulation and is known by various other names such as (metabolic)syndrome X, insulin resistance syndrome, or Reaven's syndrome. A patientdiagnosed with metabolic syndrome typical exhibits three or moresymptoms selected from the following group of five symptoms: (1)abdominal obesity; (2) hypertriglyceridemia; (3) low high-densitylipoprotein cholesterol (low HDL); (4) high blood pressure; and (5)elevated fasting glucose, which may be in the range characteristic ofType 2 diabetes. Each of these symptoms is defined in the recentlyreleased Third Report of the National Cholesterol Education ProgramExpert Panel on Detection, Evaluation and Treatment of High BloodCholesterol in Adults (Adult Treatment Panel III, or ATP III), NationalInstitutes of Health, 2001, NIH Publication No. 01-3670, hereinincorporated by reference with regard to the definition of metabolicsyndrome and its symptoms. Symptoms and features include diabetesmellitus type 2, insulin resistance, high blood pressure, fat depositsmainly around the waist, decreased HDL, elevated triglycerides, andelevated uric acid levels. Primary clinical problems are obesity and thehigh incidence of diabetes, a condition secondary to the insulinresistant state caused by excess adiposity. Insulin resistance inskeletal muscle, liver and adipose tissue impedes glucose disposal andresults in the release of free fatty acids and the characteristictriglyceride dyslipidemia associated with the metabolic syndrome.Elevations in post-prandial and ultimately fasting glucose levels resultin compensatory hyperinsulinemia, a condition which causes β-cellhypertrophy and eventual failure of the Islets and frank type 2diabetes. Different quantitative inclusion criteria for metabolicsyndrome have been proposed by the National Diabetes Federation, theWorld Health Organization, the European Group for the Study of InsulinResistance (1999) and the National Cholesterol Education Program AdultTreatment Panel III (2001). Patients with metabolic syndrome, whether ornot they have or develop overt diabetes mellitus, have an increased riskof developing the macrovascular and microvascular complications thatoccur with type 2 diabetics, such as atherosclerosis and coronary heartdisease.

In addition to the hyperglycemia experienced with diabetes mellitus andmetabolic syndrome, certain drug therapies can cause similar symptomaticeffects. Statins, otherwise referred to as3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors,are potent inhibitors of cholesterol synthesis that are extensively usedin the treatment of hypercholesterolemia. Several studies havedemonstrated the beneficial effects of statins in reducingcardiovascular morbidity and mortality. There is recent evidencehowever, from clinical and preclinical studies, that treatment withstatins has unwanted effects, including increased glycemia. See, forexample, Ohmura et al., Acute Onset and Worsening of Diabetes Concurrentwith Administration of Statins, Endocrine Journal, 52: 369-372, 2005;Sasaki et al., Statins: Beneficial or Adverse For Glucose metabolism(review), Journal of Atherosclerosis and Thrombosis 13: 123-129, 2006;Takano et al., Influence of Statins on Glucose tolerance in Patientswith Type II Diabetes mellitus, Journal of Atherosclerosis andThrombosis 13: 95-100, 2006; and Nakata et al., Effects of Statins Onthe Adipocyte Maturation and Expression of Glucose Transporter 4;Implications in Glycemic Control, Diabetologia 49: 1881-1892, 2006.

In addition to hyperglycemia, there is evidence from epidemiologicalstudies that long-term treatment with statins has unwanted effects likeincreasing the risk for Alzheimer Disease. Nicotine has been found toinhibit death of PC12 cells cultured in serum-free medium. Furthermore,the selective α7 receptor agonist, 3-(4)-dimethylaminocinnamylidineanabaseine (DMAC), and the nAChR (including the α7 subtype) activator,ABT-418, have also been reported to exert cytoprotective effects. It wasalso recently shown that nicotine activates the growth promoting enzymejanus kinase 2 (JAK2) in PC12 cells, and that pre-incubation of thesecells with the JAK2 specific inhibitor AG-490 blocks thenicotine-induced activation of neuroprotective signaling cascades.

The following references are incorporated by reference with regard to abackground understanding of relevant disease, as well as management andprevention: Banes A K, Shaw S, Jenkins J, Redd H, Amiri F, Pollock D Mand Marrero M B, Angiotensin II blockade prevents hyperglycemia-inducedactivation of JAK and STAT proteins in diabetic rat kidney glomerul, AmJ Physiol Renal Physiol 286: F653-F659, 2004; Bartholomeusz C, ItamochiH, Yuan L X, Esteva F J, Wood C G, Terakawa N, Hung M C and Ueno N T,Bcl-2 antisense oligonucleotide overcomes resistance to E1A gene therapyin a low HER2-expressing ovarian cancer xenograft model, Cancer Res 65:8406-8413, 2005; Cho-Chung Y S, Park Y G and Lee Y N, Oligonucleotidesas transcription factor decoys, Curr Opin Mol Ther 1: 386-392, 1999;Danesh F R, Sadeghi M M, Amro N, Philips C, Zeng L, Lin S, Sahai A andKanwar Y S. 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors preventhigh glucose-induced proliferation of mesangial cells via modulation ofRho GTPase/p21 signaling pathway: Implications for diabetic nephropathy,Proc Natl Acad Sci USA 99: 8301-8305, 2002; de Fiebre C M, Meyer E M,Henry J C, Muraskin S I, Kem W R and Papke R L. Characterization of aseries of anabaseine-derived compounds reveals that the3-(4)-dimethylaminocinnamylidine derivative is a selective agonist atneuronal nicotinic α7/125l-α-bungarotoxin receptor subtypes, Mol.Pharmacol. 47: 164-171, 1995; Deigner H P, Haberkorn U and Kinscherf R,Apoptosis modulators in the therapy of neurodegenerative diseases,Expert Opin. Investig. Drugs 9: 747-764, 2000; Donnelly-Roberts D L, XueI C, Arneric S P and Sullivan J P, In vitro neuroprotective propertiesof the novel cholinergic channel activator (ChCA), ABT-418, Brain Res719: 36-44, 1996; Epstein M and Campese V M, Pleiotropic effects of3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors on renalfunction; Am J Kidney Dis 45: 2-14, 2005; Garcia-Roman N, Alvarez A M,Toro M J, Montes A and Lorenzo M J, Lovastatin Induces Apoptosis ofSpontaneously Immortalized Rat Brain Neuroblasts: Involvement ofNonsterol Isoprenoid Biosynthesis Inhibition, Molecular and CellularNeuroscience 17: 329-341, 2001; Kastelein J J, The future oflipid-lowering therapy: the big picture, Neth J Med 61: 35-39, 2003;Kirito K, Watanabe T, Sawada K, Endo H, Ozawa K and Komatsu N,Thrombopoietin regulates Bcl-xL gene expression through Stat5 andphosphatidylinositol 3-kinase activation pathways, J Biol Chem 277:8329-8337, 2002; Li P, Nijhawan D, Budihardjo I, Srinivasula S M, AhmadM, Alnemri E S and Wang X, Cytochrome c and dATP-dependent formation ofApaf-1/caspase-9 complex initiates an apoptotic protease cascade, Cell91: 479-489, 1997; Li Y, Higashi Y, Itabe H, Song Y H, Du J andDelafontaine P, Insulin-Like Growth Factor-1 Receptor ActivationInhibits Oxidized LDL-Induced Cytochrome C Release and Apoptosis via thePhosphatidylinositol 3 Kinase/Akt Signaling Pathway, Arterioscler ThrombVasc Biol 23: 2178-2184, 2003; Mata P, Alonso R and Badimon J, Benefitsand risks of simvastatin in patients with familialhypercholesterolaemia, Drug Saf 26: 769-786, 2003; McKay D M, Botelho F,Ceponis P J and Richards C D, Superantigen immune stimulation activatesepithelial STAT-1 and PI 3-K: PI 3-K regulation of permeability, Am JPhysiol Gastrointest Liver Physiol 279: G1094-G1103, 2000; Meske V,Albert F, Richter D, Schwarze J and Ohm T G, Blockade of HMG-CoAreductase activity causes changes in microtubule-stabilizing protein tauvia suppression of geranylgeranylpyrophosphate formation: implicationsfor Alzheimer's disease, European Journal of Neuroscience 17: 93-102,2003; Newman M B, Arendash G W, Shytle R D, Bickford P C, Tighe T andSanberg P R, Nicotine's oxidative and antioxidant properties in CNS,Life Sciences 71: 2807-2820, 2002; Marrero M B, Papke R L, Bhatti B S,Shaw S, Bencherif M. The neuroprotective effect of2-(3-pyridyl)-1-azabicyclo[3.2.2]nonane (TC-1698), a novel alpha7ligand, is prevented through angiotensin II activation of a tyrosinephosphatase. J. Pharmacol Exp Ther. 2004 April; 309(1):16-27; YamashitaH, Nakamura S. Nicotine rescues PC12 cells from death induced by nervegrowth factor deprivation. Neurosci. Lett. 1996 Aug. 2; 213(2):145-7;Isomaa, B. A major health hazard: the metabolic syndrome. Life Sci. 73,2395-2411 (2003); Sykiotis, G. P. & Papavassiliou, A. G. Serinephosphorylation of Insulin Receptor Substrate-1: A novel target for thereversal of insulin resistance. Mol. Endocrinol. 15, 1864-1869 (2001);Dandona, P., Aljada, A. & Bandyopadhyay, A. Inflammation: the linkbetween insulin resistance, obesity and diabetes, Trends Immunol., 25,4-7 (2004); Miao, F. J. P., Green, P., Benowitz, N. & Levine, J. D.,Vagal modulation of spinal nicotine-induced inhibition of theinflammatory response mediated by descending antinociceptive controls,Neuropharmacology, 45, 605-611 (2003); Borovikova, L. V. et al., Role ofvagus nerve signaling in CNI-1493-mediated suppression of acuteinflammation, Autonomic Neurosci.: Basic and Clinical, 85, 141-147(2000); Borovikova, L. V. et al., Vagus nerve stimulation attenuates thesystemic inflammatory response to endotoxin, Nature, 405, 458-462(2000); Wang, H. et al., Nicotinic acetylcholine receptor α7 subunit isan essential regulator of inflammation, Nature, 421, 384-387 (2003); deJonge, W. J. & Ulloa, L., The alpha7 nicotinic acetylcholine receptor asa pharmacological target for inflammation, British J. Pharmacol., 151,915-929 (2007); Formari, A. et al., Nicotine withdrawal increases bodyweight, neuropeptide Y and Agouti-related protein expression in thehypothalamus and decreases uncoupling protein-3 expression in the brownadipose tissue in high-fat fed mice, Neurosci. Lett., 411, 72-76 (2007);Asante-Appiah, E. & Kennedy, B. P., Protein tyrosine phosphatases: thequest for negative regulators of insulin action, Am. J. Physiol.Endocrinol. Metabol. 284, E663-E670 (2003); Elchebly, M. et al.,Increased insulin sensitivity and obesity resistance in mice lacking theprotein tyrosine phosphatase-1B gene. Science, 283, 1544-1548 (1999);Dube, N. & Tremblay, M. L., Beyond the metabolic function of PTP1B, CellCycle, 3, 550-553 (2004); Uysal, K. T., Wiesbrock, S. M., Marino, M. W.& Hotamisligil, G. S., Protection from obesity-induced insulinresistance in mice lacking TNF-α function, Nature, 389, 610-614 (1997);Gallowitsch-Puerta, M. & Tracey, K. J., Immunologic role of thecholinergic anti-inflammatory pathway and the nicotinic acetylcholinealpha 7 receptor, Ann. N.Y. Acad. Sci. 1062, 209-19 (2005); Shaw, S.,Bencherif, M. & Marrero, M. B., Janus kinase 2, an early target of α7nicotinic acetylcholine receptor-mediated neuroprotection againstAβ-(1-42) amyloid, J. Biol. Chem., 277, 44920-44924 (2002); de Jonge, W.J. et al., Stimulation of the vagus nerve attenuates macrophageactivation by activating the Jak2-STAT3 signaling pathway, Nat.Immunol., 6, 844-51 (2005); Ahima, R. S., Qi, Y. & Singhal, N. S.,Adipokines that link obesity and diabetes to the hypothalamus, Prog.Brain Res., 153, 155-174 (2006); Kenner, K. A., Ezenta, A., Olefsky, J.M. & Kusari, J., Protein-tyrosine phosphatase 1B is a negative regulatorof Insulin-and Insulin-like Growth Factor-1-stimulated signaling, J.Biol. Chem. 271, 19810-19816 (1996); Klaman, L. D. et al., Increasedenergy expenditure, decreased adiposity, and tissue-specific insulinsensitivity in Protein-tyrosine Phosphatase 1B-deficient mice, Mol.Cell. Biol., 20, 5479-5489 (2000); Dadke, S., Kusari, J. & and Chernoff,J., Down-regulation of insulin signaling by Protein-tyrosine Phosphatase1B is mediated by an N-terminal binding region, J. Biol. Chem., 275,23642-23647 (2000); Cheng, A. et al., Attenuation of leptin action andregulation of obesity by Protein-tyrosine Phosphatase 1B, Dev. Cell, 2,497-503 (2002); Myers, M. P. et al. TYK2 and JAK2 are substrates ofProtein-tyrosine Phosphatase 1B, J. Biol. Chem., 276, 47771-47774(2001); and Bence, K. K. et al., Neuronal PTP1B regulates body weight,adiposity and leptin action, Nat. Med., 12, 917-24 (2006).

SUMMARY OF THE INVENTION

One aspect of the present invention includes a method for treating orpreventing metabolic disorders comprising the administration of aselective α7 nAChR agonist.

Another aspect of the present invention includes a method for treatingor preventing drug-induced central nervous system disorders comprisingthe administration of a selective α7 nAChR agonist.

In one embodiment, the α7 nAChR agonist is Compound A, Compound B, orCompound C, or a pharmaceutically acceptable salt thereof. In oneembodiment, the α7 nAChR agonist is Compound C or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the metabolic disorder is one or more of type Idiabetes mellitus, type II diabetes mellitus, metabolic syndrome,atherosclerosis, obesity, and hyperglycemia. In a further embodiment,the hyperglycemia is a result of statin therapy.

In one embodiment, the drug-induced central nervous system disorder is aresult of statin therapy.

One aspect of the present invention is a method for treating orpreventing a metabolic disorder comprising the administration of

or a pharmaceutically acceptable salt thereof. In one embodiment, themetabolic disorder is one or more of type I diabetes mellitus, type IIdiabetes mellitus, metabolic syndrome, atherosclerosis, obesity, andhyperglycemia. In one embodiment, a daily dose is from about 0.001 mg/kgto about 3.0 mg/kg.

One aspect of the present invention is use of a selective α7 nAChRagonist in the manufacture of a medicament for treating or preventingmetabolic disorders.

Another aspect is use of a selective α7 nAChR agonist in the manufactureof a medicament for treating or preventing drug-induced central nervoussystem disorders.

In one embodiment, the α7 nAChR agonist is Compound A, Compound B, orCompound C, or a pharmaceutically acceptable salt thereof. In oneembodiment, the α7 nAChR agonist is Compound C or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the metabolic disorder is one or more of type Idiabetes mellitus, type II diabetes mellitus, metabolic syndrome,atherosclerosis, obesity, and hyperglycemia.

In one embodiment, the hyperglycemia is a result of statin therapy. Inone embodiment, the drug-induced central nervous system disorder is aresult of statin therapy.

Another aspect of the present invention is use of Compound C:

or a pharmaceutically acceptable salt thereof in the manufacture of amedicament for treating or preventing a metabolic disorder. In oneembodiment, the metabolic disorder is one or more of type I diabetesmellitus, type II diabetes mellitus, metabolic syndrome,atherosclerosis, obesity, and hyperglycemia. In one embodiment, a dailydose is from about 0.001 mg/kg to about 3.0 mg/kg.

Another aspect of the present invention is a selective α7 nAChR agonistcompound for use in treating or preventing metabolic disorders.

Another aspect of the present invention is a selective α7 nAChR agonistcompound for use in treating or preventing drug-induced central nervoussystem disorders.

In one embodiment, the α7 nAChR agonist is Compound A, Compound B, orCompound C, or a pharmaceutically acceptable salt thereof. In oneembodiment, the α7 nAChR agonist is Compound C or a pharmaceuticallyacceptable salt thereof.

In one embodiment, the metabolic disorder is one or more of type Idiabetes mellitus, type II diabetes mellitus, metabolic syndrome,atherosclerosis, obesity, and hyperglycemia.

In one embodiment, the hyperglycemia is a result of statin therapy. Inone embodiment, the drug-induced central nervous system disorder is aresult of statin therapy.

Another aspect of the present invention is a selective α7 nAChR agonistcompound

or a pharmaceutically acceptable salt thereof for use in treating orpreventing a metabolic disorder. In one embodiment, the metabolicdisorder is one or more of type I diabetes mellitus, type II diabetesmellitus, metabolic syndrome, atherosclerosis, obesity, andhyperglycemia. In one embodiment, a daily dose is from about 0.001 mg/kgto about 3.0 mg/kg.

The scope of the present invention includes combinations of aspects,embodiments, and preferences herein described.

BRIEF DESCRIPTION OF THE FIGURES

The Figures describe results obtained according to particularembodiments of the invention and exemplify aspects of the invention butshould not be construed to be limiting.

FIG. 1 is a graphic representation showing the effects of Compound A onbody weight in obese db/db mice.

FIG. 2 is a graphic representation showing the effects of Compound A onplasma glucose in obese db/db mice.

FIG. 3 is a graphic representation showing the effects of Compound A onfood consumption in obese db/db mice.

FIG. 4 is a graphic representation showing the effects of Compound A onbody weight in obese db/db mice.

FIG. 5 is a graphic representation showing the effects of Compound A onglucose levels in obese db/db mice.

FIG. 6 is a graphic representation showing the partial inhibition of theeffects of Compound A on food consumption in obese db/db mice of theJAK2 tyrosine phosphorylation inhibitor AG-490. AG-490, a knowninhibitor of JAK2 tyrosine phosphorylation, partially inhibits effectsof Compound A.

FIGS. 7A and 7B are graphic representations showing the effects of JAK2loss-of-function on multiple low dose (MLDS) STZ-induced diabetes(Fasting Blood Glucose) in mice in the presence or absence of CompoundA.

FIGS. 8A and 8B are graphic representations showing the effects of JAK2loss-of-function on multiple low dose (MLDS) STZ-induced increase inHbA1c in mice in the presence or absence of Compound A.

FIGS. 9A and 9B are graphic representations showing the effects of JAK2loss-of-function on multiple low dose (MLDS) STZ-induced decrease inplasma insulin in mice in the presence or absence of Compound A.

FIGS. 10A and 10B are graphic representations showing the effects ofJAK2 loss-of-function on multiple low dose (MLDS) STZ-induced increasein plasma TNFα in mice in the presence or absence of Compound A.

FIG. 11 is a graphic representation showing the effects of Compound B onfood consumption in db/db mice. Results represent the mean+/−SEM ofeight treated mice and are expressed as food consumed in grams/day. Fatmice show a significant increase in food consumption (*P<0.01) which wassignificantly inhibited by Compound B treatment (+P<0.01).

FIG. 12 is a graphic representation showing the effects of Compound B onbody mass in db/db mice. Results represent the mean+/−SEM of eighttreated mice and are expressed as their body mass in grams. Fat miceshow a significant increase in body mass (*P<0.01) which wassignificantly inhibited by Compound B (+P<0.01).

FIG. 13 is a graphic representation showing the effects of Compound B onplasma blood glucose (BG) in db/db mice. Results represent themean+/−SEM of eight treated mice and are expressed as mg/dL. Fat miceshow a significant increase in BG (*P<0.01) which was significantlyinhibited by Compound B treatment (+P<0.01).

FIG. 14 is a graphic representation showing the effects of Compound B onplasma triglycerides (TG) in db/db mice. Results represent themean+/−SEM of eight treated mice and are expressed as mg/dL. Fat miceshow a significant increase in plasma TG (*P<0.01) which wassignificantly inhibited by Compound B treatment (+P<0.01).

FIG. 15 is a graphic representation showing the effects of Compound B onplasma glycosylated hemoglobin (Hb1ac) in db/db mice. Results representthe mean+/−SEM of five treated mice and are expressed as %. Fat miceshow a significant increase in plasma HbA1c (*P<0.01) which wassignificantly inhibited by Compound B treatment (+P<0.01).

FIG. 16 is a graphic representation showing the effects of Compound B onplasma TNFα in db/db mice. Results represent the mean+/−SEM of fivetreated mice and are expressed as pg/ml. Fat mice show a significantincrease in TNFα (*P<0.01) which was significantly inhibited by CompoundB treatment (+P<0.01).

FIG. 17 is a graphic representation showing the effects of Compound B onthe Glucose Tolerance Test (GTT) in db/db mice PTP-1B WT mice. Resultsrepresent the mean+/−SEM of four treated mice and are expressed asmg/dL. Fat mice show a significant increase in glucose levels(*P<0.01)and a significant effect with Compound B treatment (+P<0.01).

FIG. 18 is a graphic representation of the effects of simvastatin,referred generally as “statin,” and Compound A on body mass in db/dbmice. Results represent the mean+/−SEM of eight treated mice and areexpressed as their body mass in grams. Fat mice show a significantincrease in body mass (*P<0.01) which was significantly inhibited byCompound A (+P<0.01). Simvastatin alone did not significantly inhibitthe increase in body mass (#P>0.05). However, the combination ofsimvastatin and Compound A had a significant effect in lowering the bodymass compared to simvastatin alone (**P<0.01).

FIG. 19 is a graphic representation of the effects of simvastatin,referred generally as “statin,” and Compound A on food consumption indb/db mice. Results represent the mean+/−SEM of eight treated mice andare expressed as food consumed in grams/day. Fat mice show a significantincrease in food consumption (*P<0.01) which was significantly inhibitedby Compound A (+P<0.01). Simvastatin alone did not significantlyinhibited the increased in food consumption (#P>0.05). However, thecombination of simvastatin and Compound A had a significant effect(**P<0.01).

FIG. 20 is a graphic representation of the effects of simvastatin,referred generally as “statin,” and Compound A on Hb1ac in db/db mice.Results represent the mean+/−SEM of eight treated mice and are expressedas % glycated hemoglobin (% Hb1 ac). Fat mice show a significantincrease in % Hb1 ac (*P<0.01) which was significantly inhibited byCompound A (+P<0.01). Simvastatin alone did not lower the levels %Hb1ac. On the other hand, it significantly increased the levels of %Hb1ac (++P<0.01) above the fat mice treated with vehicle alone. Thecombination of simvastatin and Compound A significantly decreased thelevels of % Hb1 ac when compared to both the fat (**P<0.01) and the fatplus simvastatin (#P<0.01).

FIG. 21 is a graphic representation of the effects of simvastatin,referred generally as “statin,” and Compound A on plasma blood glucose(BG) in db/db mice. Results represent the mean+/−SEM of eight treatedmice and are expressed as mg/dL. Fat mice show a significant increase inBG (*P<0.01) which was significantly inhibited by Compound A (+P<0.01).Simvastatin alone significantly increased the levels of BG (++P<0.01)above the fat mice treated with vehicle alone. However, the combinationof simvastatin and Compound A significantly decreased the levels of BGwhen compared to both the fat (**P<0.01) and the fat plus simvastatin(#P<0.01).

FIGS. 22A and 22B are graphic representations of the effects ofsimvastatin, referred generally as “statin,” and Compound A on insulinresistance glucose tolerance test in db/db mice.

FIG. 23 is a graphic representation of the effects of simvastatin,referred generally as “statin,” and Compound A on plasma triglycerides(TG) in db/db mice. Results represent the mean+/−SEM of eight treatedmice and are expressed as mg/dL. Fat mice show a significant increase inTG (*P<0.01) which was significantly inhibited by Compound A (+P<0.01).Simvastatin alone did not significantly decreased the levels of TG(++P>0.01) above the fat mice treated with vehicle alone. However, thecombination of simvastatin and Compound A significantly decreased thelevels of TG when compared to both the fat and the fat (**P<0.01) andthe fat plus simvastatin (#P<0.01).

FIG. 24 is a graphic representation of the effects of simvastatin,referred generally as “statin,” and Compound A on plasma cholesterol(Chol) in db/db mice. Results represent the mean+/−SEM of eight treatedmice and are expressed as mg/dL. Fat mice show a significant increase inChol (*P<0.01) which was significantly inhibited by Compound A(+P<0.01). Simvastatin alone also significantly decreased the levels ofChol (++P>0.01) above the fat mice treated with vehicle alone. Thecombination of simvastatin and Compound A also significantly decreasedthe levels of Chol when compared to the fat (**P<0.01). However, therewas no significant difference between the Compound A plus simvastatinand the simvastatin alone (#P>0.05).

FIG. 25 is a graphic representation of the effects of simvastatin,referred generally as “statin,” and Compound A on plasma TNFα in db/dbmice. Results represent the mean+/−SEM of eight treated mice and areexpressed as pg/ml. Fat mice show a significant increase in TNFα(*P<0.01) which was significantly inhibited by Compound A (+P<0.01).Simvastatin alone did not significantly inhibit the increased in TNFα(#P>0.05). However, the combination of simvastatin and Compound A had asignificant effect in lowering the levels of TNFa (**P<0.01).

FIG. 26A is an illustration of the identification of hippocampalprogenitor cells using flow cytometry.

FIG. 26B is a graphic representation of the effect of anti-depressantson hippocampal progenitor proliferation in mice.

FIG. 27 is a graphic representation of the effect of Compound A onhippocampal progenitor cell proliferation.

FIG. 28 is a graphic representation illustrating a microglial cellproliferation assay. P FIG. 29 is a graphic representation of theeffects of nicotine, Compound D, Compound E, and Compound A onmicroglial cell proliferation in an LPS-induced model ofneuroinflammation.

FIG. 30 is a is a Western blot showing the effects of simvastatin on thenicotine-induced JAK2 activation in PC12 cells. Cells were pretreatedwith simvastatin (5 uM) for 24 hours and with nicotine at the timeindicated. The methods for blotting are as described (see, Shaw S. etal, J. Biol. Chem., 2002, herein incorporated by reference).Pretreatment of cells with simvastatin significantly inhibited JAK2activation induced by nicotine for the times indicated.

FIG. 31 is a Western blot showing the effects of simvastatin on thenicotine-induced neuroprotection against Aβ-induced apoptosis in PC12cells. The methods are as described. Poly-(ADP-ribose) polymerase (PARP)is marker of cells undergoing apoptosis. PARP expression was determinedby Western analysis of PC12 cells nuclear extract.

FIG. 32 is a Western blot showing the effects of 10 μM farnesylpyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) on thesimvastatin-induced apoptosis in PC12 cells. The methods are asdescribed.

FIG. 33 is graphic representation showing the effects of 10 μM farnesylpyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) on thesimvastatin blockade of nicotine-induced ROS production in PC12 cells.

FIG. 34 is a graphic representation of the effects of Compound C on foodconsumption in db/db mice. The illustrated results represent themean±SEM of five treated mice/group and are expressed as food consumedin grams/day. Fat mice show a significant increase in food consumptionabove lean mice (*P<0.01) which was significantly inhibited by CompoundC treatment (+P<0.01). There is no significant difference between fatwild type and fat PTP-1B KO mice in decreased food consumption due toCompound C treatment (#P>0.05).

FIG. 35 is a graphic representation of the effects of Compound C on bodymass in db/db mice. The illustrated results represent the mean±SEM offive treated mice/group and are expressed as body mass in grams. Fatmice show a significant increase in body mass (*P<0.01) which wassignificantly inhibited by Compound C treatment (+P<0.01). There is nosignificant difference between fat wild type and fat PTP-1B KO mice dueto Compound C treatment (#P>0.05).

FIG. 36 is a graphic representation of the effects of Compound C onplasma blood glucose (BG) in db/db mice. The illustrated resultsrepresent the mean±SEM of five treated mice/group and are expressed asmg/dL of BG. Fat mice show a significant increase in BG (*P<0.01) whichwas significantly inhibited by Compound C treatment (+P<0.01). There isno significant difference between fat wild type and fat PTP-1B KO micedue to Compound C treatment (#P>0.05).

FIG. 37 is a graphic representation of the effects of Compound C onplasma triglycerides in db/db mice. The illustrated results representthe mean±SEM of five treated mice/group and are expressed as mg/dL. Fatmice show a significant increase in plasma TG (*P<0.01) which wassignificantly inhibited by Compound C treatment (+P<0.01) in the fatPTP-1B wild type but not in the fat PTP-1B KO. There is also asignificant difference in plasma TG levels between the treated fat wildtype and treated fat PTP-1B KO (#P<0.01).

FIG. 38 is a graphic representation of the effects of Compound C onplasma glycosylated hemoglobin (Hb1ac) in db/db mice. The illustratedresults represent the mean±SEM of five treated mice/group and areexpressed as %. Fat mice show a significant increase in plasma Hb1ac(*P<0.01) which was significantly inhibited by Compound C treatment(+P<0.01). There is no significant difference in plasma Hb1ac betweenfat PTP-1B wild type and fat PTP-1B KO (#P>0.05).

FIG. 39 is a graphic representation of the effects of Compound C on TNFαin db/db mice. The illustrated results represent the mean±SEM of fivetreated mice/group and are expressed as pg/mL. Fat mice show asignificant increase in TNFα (*P<0.01) which was significantly inhibitedby Compound C treatment (+P<0.01). There is a significant differencebetween TNFα plasma levels between the fat wild type and fat PTP-1B KO(#P<0.01).

FIG. 40 is a graphic representation of the effects of Compound C in theglucose tolerance test (GTT) in db/db mice PTP-1B wild type mice. Theillustrated results represent the mean±SEM of four treated mice/groupand are expressed as mg/dL. Fat mice show a significant decrease inglucose deposition (*P<0.01) with Compound C treatment. Fat mice show asignificant increase in deposition (+P<0.01).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

One aspect of the present invention includes the role of α7 nAChRs inregulating key biological pathways involved in the metabolic syndromeand the potential of selective α7 nAChR agonists as a novel therapeuticapproach to treat this condition. Although α7 has been implicated in thecholinergic inflammatory pathway, the evidence is based exclusively onthe use of non-selective agonists in the presence of putative selectiveantagonists, some with rather poor pharmacokinetics or brain penetrationproperties. Thus, another aspect of the present invention includescompounds (hereinafter defined and referred to as Compounds A, B, or C)with high selectivity for the α7 nAChR.

Compound A is(5-methyl-N-[(2S,3R)-2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide),illustrated below.

or a pharmaceutically acceptable salt thereof. As will be appreciated,alternate naming conventions provide alternative names. Thus, Compound Amay also be referred to as(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)-5-methylthiophene-2-carboxamide.Such naming conventions should not impact the clarity of the presentinvention.

Compound B is(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-(2-pyridinyl)thiophene-2-carboxamide,illustrated below:

or a pharmaceutically acceptable salt thereof.

Compound C is(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide,illustrated below:

or a pharmaceutically acceptable salt thereof.

In the studies of this application, evidence is presented showing thatα7-selective ligands inhibit the metabolic syndrome observed in db/dbmice by reducing weight gain, normalizing glucose levels, increasinginsulin secretion, decreasing glycated hemoglobin, reducingpro-inflammatory cytokines, reducing triglycerides, and normalizinginsulin resistance glucose tolerance test. These data indicate thatα7-selective ligands are useful for the management of the metabolicsyndrome (diabetes I and II, atherosclerosis, obesity).

Another aspect of the present invention provides methods andcompositions relating to co-administration of α7 selective ligands withstatins, in order to decrease unwanted side effects of statins,including increased glycemia. Relevant statins include atorvastatin,cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin,pravastatin, rosuvastatin, simvastatin, and additional statins, definedbased on their inhibition of HMG CoA reductase. Although trade names orgeneric names may be used herein, reference is had to the underlyingactive ingredient(s) in such drug products.

Compounds

Compounds useful according to the present invention are α7 NNR selectiveligands, as exemplified by Compounds A, B, and C, herein.

Compounds A, B and C are members of a genus of compounds described inU.S. Pat. No. 6,953,855 (incorporated herein by reference in itsentirety). U.S. Pat. No. 6,953,855 includes compounds represented byFormula 1.

In Formula 1, m and n individually can have a value of 1 or 2, and p canhave a value of 1, 2, 3 or 4. In the Formula, X is either oxygen ornitrogen (i.e., NR′), Y is either oxygen or sulfur, and Z is eithernitrogen (i.e., NR′), a covalent bond or a linker species, A. A isselected from the group —CR′ R″-, —CR′ R″—CR′ R″-, —CR′═CR′-, and —C₂—,wherein R′ and R″ are as hereinafter defined. When Z is a covalent bondor A, X must be nitrogen. Ar is an aryl group, either carbocyclic orheterocyclic, either monocyclic or fused polycyclic, unsubstituted orsubstituted; and Cy is a 5- or 6-membered heteroaromatic ring,unsubstituted or substituted. Thus, the invention includes compounds inwhich Ar is linked to the azabicycle by a carbonyl group-containingfunctionality, such as an amide, carbamate, urea, thioamide,thiocarbamate or thiourea functionality. In addition, in the case of theamide and thioamide functionalities, Ar may be bonded directly to thecarbonyl (or thiocarbonyl) group or may be linked to the carbonyl (orthiocarbonyl) group through linker A. Furthermore, the inventionincludes compounds that contain a 1-azabicycle, containing either a 5-,6-, or 7-membered ring and having a total of 7, 8 or 9 ring atoms (e.g.,1-azabicyclo[2.2.1]heptane, 1-azabicyclo[3.2.1]octane,1-azabicyclo[2.2.2]octane, and 1-azabicyclo[3.2.2]nonane).

In one embodiment, the value of p is 1, Cy is 3-pyridinyl or5-pyrimidinyl, X and Y are oxygen, and Z is nitrogen. In anotherembodiment, the value of p is 1, Cy is 3-pyridinyl or 5-pyrimidinyl, Xand Z are nitrogen, and Y is oxygen. In a third embodiment, the value ofp is 1, Cy is 3-pyridinyl or 5-pyrimidinyl, X is nitrogen, Y is oxygen,and Z is a covalent bond (between the carbonyl and Ar). In a fourthembodiment, the value of p is 1, Cy is 3-pyridinyl or 5-pyrimidinyl, Xis nitrogen, Y is oxygen, Z is A (a linker species between the carbonyland Ar).

The compounds of Formula 1 have one or more asymmetric carbons and cantherefore exist in the form of racemic mixtures, enantiomers anddiastereomers. Both relative and absolute stereochemistry at asymmetriccarbons are variable (e.g., cis or trans, R or S). In addition, some ofthe compounds exist as E and Z isomers about a carbon-carbon doublebond. All these individual isomeric compounds and their mixtures arealso intended to be within the scope of Formula 1.

As used in Formula 1, Ar (“aryl”) includes both carbocyclic andheterocyclic aromatic rings, both monocyclic and fused polycyclic, wherethe aromatic rings can be 5- or 6-membered rings. Representativemonocyclic aryl groups include, but are not limited to, phenyl, furanyl,pyrrolyl, thienyl, pyridinyl, pyrimidinyl, oxazolyl, isoxazolyl,pyrazolyl, imidazolyl, thiazolyl, isothiazolyl and the like. Fusedpolycyclic aryl groups are those aromatic groups that include a 5- or6-membered aromatic or heteroaromatic ring as one or more rings in afused ring system. Representative fused polycyclic aryl groups includenaphthalene, anthracene, indolizine, indole, isoindole, benzofuran,benzothiophene, indazole, benzimidazole, benzthiazole, purine,quinoline, isoquinoline, cinnoline, phthalazine, quinazoline,quinoxaline, 1,8-naphthyridine, pteridine, carbazole, acridine,phenazine, phenothiazine, phenoxazine, and azulene.

As used in Formula 1, “Cy” groups are 5- and 6-membered ringheteroaromatic groups. Representative Cy groups include pyridinyl,pyrimidinyl, furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl,pyrazolyl, imidazolyl, thiazolyl, isothiazolyl and the like, wherepyridinyl is preferred.

Individually, Ar and Cy can be unsubstituted or can be substituted with1, 2 or 3 substituents, such as alkyl, alkenyl, heterocyclyl,cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,halo (e.g., F, Cl, Br, or I), —OR′, —NR′R″, —CF₃, —CN, —NO₂, —C₂R′,—SR′, —N₃, —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′,—O(CR′R″)_(r)C(═O)R′, —O(CR′R″)_(r)NR′C(═O)R′, —O(CR′R″)_(r)NR′SO₂R′,—OC(═O)NR′R″, —NR′C(═O)O R″, —SO₂R′, —SO₂NR′R″, and —NR′SO₂R″, where R′and R″ are individually hydrogen, C₁-C₈ alkyl (e.g., straight chain orbranched alkyl, preferably C₁-C₅, such as methyl, ethyl, or isopropyl),cycloalkyl (e.g., C₃₋₈ cyclic alkyl), heterocyclyl, aryl, or arylalkyl(such as benzyl), and r is an integer from 1 to 6. R′ and R″ can alsocombine to form a cyclic functionality.

Compounds of Formula 1 form acid addition salts which are usefulaccording to the present invention. Examples of suitablepharmaceutically acceptable salts include inorganic acid addition saltssuch as chloride, bromide, sulfate, phosphate, and nitrate; organic acidaddition salts such as acetate, galactarate, propionate, succinate,lactate, glycolate, malate, tartrate, citrate, maleate, fumarate,methanesulfonate, p-toluenesulfonate, and ascorbate; salts with acidicamino acid such as aspartate and glutamate. The salts may be in somecases hydrates or ethanol solvates.

Representative compounds of Formula 1 include:

-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-phenylcarbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(4-fluorophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(4-chlorophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(4-bromophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(3-fluorophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(3-chlorophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(3-bromophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(2-fluorophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(2-chlorophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(2-bromophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(3,4-dichlorophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(2-methylphenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(2-biphenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(3-methylphenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(3-biphenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(4-methylphenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(4-biphenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(2-cyanophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(3-cyanophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(4-cyanophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(3-trifluoromethylphenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(4-dimethylaminophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(2-methoxyphenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(2-phenoxyphenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(2-methylthiophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(2-phenylthiophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(3-methoxyphenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(3-phenoxyphenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(3-methylthiophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(3-phenylthiophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(4-methoxyphenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(4-phenoxyphenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(4-methylthiophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(4-phenylthiophenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(2,4-dimethoxyphenyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(2-thienyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(3-thienyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(3-benzothienyl)carbamate,-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(1-naphthyl)carbamate, and-   2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl    N-(2-naphthyl)carbamate.

Other compounds representative of Formula 1 include:

-   N-phenyl-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(4-fluorophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(4-chlorophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(4-bromophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(3-fluorophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(3-chlorophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(3-bromophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(2-fluorophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(2-chlorophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(2-bromophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(3,4-dichlorophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(2-methylphenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(2-biphenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(3-methylphenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(3-biphenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(4-methylphenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(4-biphenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(2-cyanophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(3-cyanophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(4-cyanophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(3-trifluoromethylphenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(4-dimethylaminophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(2-methoxyphenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(2-phenoxyphenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(2-methylthiophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(2-phenylthiophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(3-methoxyphenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(3-phenoxyphenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(3-methylthiophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(3-phenylthiophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(4-methoxyphenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(4-phenoxyphenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(4-methylthiophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(4-phenylthiophenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(2,4-dimethoxyphenyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(2-thienyl)-N′-(2-((3-pyridinyl)methyl)-1-aza    bicyclo[2.2.2]oct-3-yl)urea,-   N-(3-thienyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(3-benzothienyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,-   N-(1-naphthyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea,    and-   N-(2-naphthyl)-N′-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)urea.

Other compounds representative of Formula 1 include:

-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-2-fluorobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-fluorobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-4-fluorobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-2-chlorobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-chlorobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-4-chlorobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-2-bromobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-bromobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-4-bromobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,4-dichlorobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-2-methylbenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-methylbenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-4-methylbenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-2-phenylbenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-phenylbenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-4-phenylbenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-2-cyanobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-cyanobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-4-cyanobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-trifluoromethylbenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-4-dimethylaminobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-2-methoxybenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-methoxybenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-4-methoxybenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-2-phenoxybenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-phenoxybenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-4-phenoxybenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-2-methylthiobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-methylthiobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-4-methylthiobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-2-phenylthiobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-phenylthiobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-4-phenylthiobenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-2,4-dimethoxybenzamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-bromonicotinamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-6-chloronicotinamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-phenylnicotinamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)furan-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)furan-3-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)thiophene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-bromothiophene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiothiophene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-phenylthiothiophene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-methylthiophene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-bromothiophene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-chlorothiophene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-(2-pyridinyl)thiophene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-acetylthiophene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-ethoxythiophene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-methoxythiophene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-aza    bicyclo[2.2.2]oct-3-yl)-4-acetyl-3-methyl-5-methylthiothiophene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)thiophene-3-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-1-methylpyrrole-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)pyrrole-3-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)indole-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)indole-3-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-1-methyl    indole-3-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-1-benzylindole-3-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-1H-benzimidazole-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-1-isopropyl-2-trifluoromethyl-1H-benzimidazole-5-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-1-isopropyl-1H-benzotriazole-5-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzo[b]thiophene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzo[b]thiophene-3-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-3-carboxamide,-   N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)-3-methylbenzofuran-2-carboxamide,-   N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)-5-nitrobenzofuran-2-carboxamide,-   N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)-5-methoxybenzofuran-2-carboxamide,-   N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)-7-methoxybenzofuran-2-carboxamide,-   N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)-7-ethoxybenzofuran-2-carboxamide,-   N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)-3-methyl-5-chlorobenzofuran-2-carboxamide,-   N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)-6-bromobenzofuran-2-carboxamide,-   N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)-4-acetyl-7-methoxybenzofuran-2-carboxamide,-   N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)-2-methylbenzofuran-4-carboxamide,-   N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)naphtho[2,1-b]furan-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)naphthalene-1-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)naphthalene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-6-aminonaphthalene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)-3-methoxynaphthalene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)-6-methoxynaphthalene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)-1-hydroxynaphthalene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)-6-hydroxynaphthalene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)-6-acetoxynaphthalene-2-carboxamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-phenylprop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(3-fluorophenyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(4-methoxyphenyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-2-methyl-3-phenylprop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(2-fluorophenyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(3-methylphenyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(4-fluorophenyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(4-methylphenyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(2-furyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(2-methoxyphenyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(3-bromophenyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(3-methoxyphenyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(3-hydroxyphenyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(4-bromophenyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(4-chlorophenyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(4-hydroxyphenyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(4-hydroxy-3-methoxyphenyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(2-thienyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(3-pyridinyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(4-biphenyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(1-naphthyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(3-thienyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(4-isopropylphenyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-methyl-3-phenylprop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(3-furyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-2-ethyl-3-phenylprop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(2-pyridinyl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(3,4-dimethylthieno[2,3-b]thiophen-2-yl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(3-methylthien-2-yl)prop-2-enamide,-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(2-naphthyl)prop-2-enamide,    and-   N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3-(4-methylthiophenyl)prop-2-enamide.

A second genus of α7 NNR selective ligands (see U.S. application Ser.No. 11/465,914, Pub. No. 2007 00197579 A1; also see publishedinternational application WO 2007/024814 A1; each of which isincorporated herein by reference in its entirety), useful according tothe present invention, is represented by Formula 2.

In Formula 2, Y is either oxygen or sulfur, and Z is either nitrogen(i.e., NR′) or a covalent bond. A is either absent or a linker speciesselected from the group —CR′ R″-, —CR′R″—CR′ R″-, —CR′═CR′-, and —C₂—,wherein R′ and R″ are as hereinafter defined. Ar is an aryl group,either carbocyclic or heterocyclic, either monocyclic or fusedpolycyclic, unsubstituted or substituted; and Cy is a 5- or 6-memberedheteroaromatic ring, unsubstituted or substituted. Thus, the inventionincludes compounds in which Ar is linked to the diazatricycle, at thenitrogen of the pyrrolidine ring, by a carbonyl group-containingfunctionality, forming an amide or a urea functionality. Ar may bebonded directly to the carbonyl group-containing functionality or may belinked to the carbonyl group-containing functionality through linker A.Furthermore, the invention includes compounds that contain adiazatricycle, containing a 1-azabicyclo[2.2.2]octane. As used inreference to Formula 2, a “carbonyl group-containing functionality” is amoiety of the formula —C(═Y)—Z—, where Y are Z are as defined herein.

In one embodiment, Cy is 3-pyridinyl or 5-pyrimidinyl, Y is oxygen, Z isa covalent bond and A is absent. In another embodiment, Cy is3-pyridinyl or 5-pyrimidinyl, Y is oxygen, Z is nitrogen and A isabsent. In a third embodiment, Cy is 3-pyridinyl or 5-pyrimidinyl, Y isoxygen, Z is a covalent bond, and A is a linker species. In a fourthembodiment, Cy is 3-pyridinyl or 5-pyrimidinyl, Y is oxygen, Z isnitrogen and A is a linker species.

The junction between the azacycle and the azabicycle can becharacterized by any of the various relative and absolute stereochemicalconfigurations at the junction sites (e.g., cis or trans, R or S). Thecompounds have one or more asymmetric carbons and can therefore exist inthe form of racemic mixtures, enantiomers and diastereomers. Inaddition, some of the compounds exist as E and Z isomers about acarbon-carbon double bond. All these individual isomeric compounds andtheir mixtures are also intended to be within the scope of the presentinvention.

As used in Formula 2, Ar (“aryl”) includes both carbocyclic andheterocyclic aromatic rings, both monocyclic and fused polycyclic, wherethe aromatic rings can be 5- or 6-membered rings. Representativemonocyclic aryl groups include, but are not limited to, phenyl, furanyl,pyrrolyl, thienyl, pyridinyl, pyrimidinyl, oxazolyl, isoxazolyl,pyrazolyl, imidazolyl, thiazolyl, isothiazolyl and the like. Fusedpolycyclic aryl groups are those aromatic groups that include a 5- or6-membered aromatic or heteroaromatic ring as one or more rings in afused ring system. Representative fused polycyclic aryl groups includenaphthalene, anthracene, indolizine, indole, isoindole, benzofuran,benzothiophene, indazole, benzimidazole, benzthiazole, purine,quinoline, isoquinoline, cinnoline, phthalazine, quinazoline,quinoxaline, 1,8-naphthyridine, pteridine, carbazole, acridine,phenazine, phenothiazine, phenoxazine, and azulene.

As used in Formula 2, “Cy” groups are 5- and 6-membered ringheteroaromatic groups. Representative Cy groups include pyridinyl,pyrimidinyl, furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl,pyrazolyl, imidazolyl, thiazolyl, isothiazolyl and the like, wherepyridinyl is preferred.

Individually, Ar and Cy can be unsubstituted or can be substituted with1, 2 or 3 substituents, such as alkyl, alkenyl, heterocyclyl,cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,halo (e.g., F, Cl, Br, or I), —OR′, —NR′R″, —CF₃, —CN, —NO₂, —C₂R′,—SR', —N₃, —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′,—O(CR′R″)_(r)C(═O)R′, —O(CR′R″)_(r)NR′C(═O)R′, —O(CR′R″)_(r)NR′SO₂R′,—OC(═O)NR′R″, —NR′C(═O)OR″, —SO₂R′, —SO₂NR′R″, and —NR′SO₂R″, where R′and R″ are individually hydrogen, C₁-C₈ alkyl (e.g., straight chain orbranched alkyl, preferably C₁-C₅, such as methyl, ethyl, or isopropyl),cycloalkyl (e.g., C₃₋₈ cyclic alkyl), heterocyclyl, aryl, or arylalkyl(such as benzyl), and r is an integer from 1 to 6. R′ and R″ can alsocombine to form a cyclic functionality.

Compounds of Formula 2 form acid addition salts which are usefulaccording to the present invention. Examples of suitablepharmaceutically acceptable salts include inorganic acid addition saltssuch as chloride, bromide, sulfate, phosphate, and nitrate; organic acidaddition salts such as acetate, galactarate, propionate, succinate,lactate, glycolate, malate, tartrate, citrate, maleate, fumarate,methanesulfonate, p-toluenesulfonate, and ascorbate; salts with acidicamino acid such as aspartate and glutamate. The salts may be in somecases hydrates or ethanol solvates.

Representative compounds of Formula 2 include:

-   5-benzoyl-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(2-fluorobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(3-fluorobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(4-fluorobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(2-chlorobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(3-chlorobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(4-chlorobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(2-bromobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(3-bromobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(4-bromobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(2-iodobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(3-iodobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(4-iodobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(2-methylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(3-methylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(4-methylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(2-methoxybenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(3-methoxybenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(4-methoxybenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(2-methylthiobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(3-methylthiobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(4-methylthiobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(2-phenylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(3-phenylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(4-phenylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(2-phenoxybenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(3-phenoxybenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(4-phenoxybenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(2-phenylthiobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(3-phenylthiobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(4-phenylthiobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(2-cyanobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(3-cyanobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(4-cyanobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(2-trifluoromethylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(3-trifluoromethylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(4-trifluoromethylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(2-dimethylaminobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(3-dimethylaminobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(4-dimethylaminobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(2-ethynylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(3-ethynylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(4-ethynylbenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(3,4-dichlorobenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(2,4-dimethoxybenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(3,4,5-trimethoxybenzoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(naphth-1-ylcarbonyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(naphth-2-ylcarbonyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(thien-2-ylcarbonyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(thien-3-ylcarbonyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(furan-2-ylcarbonyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(benzothien-2-ylcarbonyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(benzofuran-2-ylcarbonyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(7-methoxybenzofuran-2-ylcarbonyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,    and-   5-(1H-Indol-3-ylcarbonyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane.

Other compounds representative of Formula 2 include:

-   5-(phenylacetyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(diphenylacetyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(2-phenylpropanoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,    and-   5-(3-phenylprop-2-enoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane.-   Other compounds representative of Formula 2 include:-   5-N-phenylcarbamoyl-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(2-fluorophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(3-fluorophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(4-fluorophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(2-chlorophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(3-chlorophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(4-chlorophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(2-bromophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(3-bromophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(4-bromophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(2-iodophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(3-iodophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(4-iodophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(2-methylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(3-methylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(4-methylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(2-methoxyphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(3-methoxyphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(4-methoxyphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(2-methylthiophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(3-methylthiophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(4-methylthiophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(2-phenylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(3-phenylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(4-phenylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(2-phenoxyphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(3-phenoxyphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(4-phenoxyphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(2-phenylthiophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(3-phenylthiophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(4-phenylthiophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(2-cyanophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(3-cyanophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(4-cyanophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(2-trifluoromethylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(3-trifluoromethylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(4-trifluoromethylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(2-dimethylaminophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(3-dimethylaminophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(4-dimethylaminophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(2-ethynylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(3-ethynylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(4-ethynylphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(3,4-dichlorophenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(2,4-dimethoxyphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(3,4,5-trimethoxyphenyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(1-naphthyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,    and-   5-(N-(2-naphthyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane.

Other compounds representative of Formula 2 include:

-   5-(N-benzylcarbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(4-bromobenzyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(4-methoxybenzyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,-   5-(N-(1-phenylethyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane,    and-   5-(N-(diphenylmethyl)carbamoyl)-3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane.

In each of these compounds, a3-pyridin-3-yl-1,5-diazatricyclo[5.2.2.0<2,6>]undecane moiety has thestructure, with a partial numbering scheme provided, shown below:

The nitrogen at the position indicated above as the 5-position is thenitrogen involved in the formation of the amides, thioamides, ureas andthioureas described herein.

Compounds useful according to the present invention also includecompounds of Formula 3:

In Formula 3, X is either oxygen or nitrogen (i.e., NR′), and Z iseither nitrogen (i.e., NR′), —CR′═CR′- or a covalent bond, provided thatX must be nitrogen when Z is —CR′═CR′- or a covalent bond, and furtherprovided that X and Z are not simultaneously nitrogen. Ar is an arylgroup, either carbocyclic or heterocyclic, either monocyclic or fusedpolycyclic, unsubstituted or substituted; R′ is hydrogen, C₁-C₈ alkyl(e.g., straight chain or branched alkyl, preferably C₁-C₅, such asmethyl, ethyl, or isopropyl), aryl, or arylalkyl (such as benzyl).

Compounds in which X is oxygen and Z is nitrogen are disclosed as α7selective ligands in, for instance, PCT WO 97/30998 and U.S. Pat. No.6,054,464, each of which is incorporated herein in its entirety.

Compounds in which X is nitrogen and Z is covalent bond are disclosed asα7 selective ligands in, for instance, PCTs WO 02/16355, WO 02/16356, WO02/16358, WO 04/029050, WO 04/039366, WO 04/052461, WO 07/038,367, andin U.S. Pat. No. 6,486,172, U.S. Pat. No. 6,500,840, U.S. Pat. No.6,599,916, U.S. Pat. No. 7,001,914, U.S. Pat. No. 7,067,515, and U.S.Pat. No. 7,176,198, each of which is herein incorporated herein in itsentirety.

Compounds in which X is nitrogen and Z is —CR′═CR′- are disclosed as α7selective ligands in, for instance, PCT WO 01/036417 and U.S. Pat. No.6,683,090, each of which is incorporated herein in its entirety.

Particular embodiments according to the general Formula 3 include thefollowing:

-   N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-phenylthiophene-2-carboxamide;-   N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-2-phenyl-1,3-thiazole-5-carboxamide;-   N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-phenyl-1,3-oxazole-2-carboxamide;-   N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-phenyl-1,3,4-oxadiazole-2-carboxamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-y-l]-4-(4-hydroxyphenoxy)benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-acetamidophenoxy)benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-phenoxybenzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-benzylbenzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(phenylsulfanyl)benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-phenoxybenzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-benzoylbenzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-fluorophenoxy)benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-fluorophenoxy)benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-fluorophenoxy)benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-chlorophenoxy)benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenoxy)benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-chlorophenoxy)benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-methoxyphenoxy)benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-methoxyphenoxy)benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-methoxyphenoxy)benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenylsulfanyl)benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-methoxyphenoxy)benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenylsulfanyl)benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-chlorophenylsulfanyl)benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-methoxyphenylsulfanyl)-benzamide;-   N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(2-methoxyphenylsulfanyl)-benzamide;-   N-(2-methyl-1-azabicyclo[2.2.2]oct-3-yl)-4-phenoxybenzamide;-   N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-4-(pyridin-3-yloxy)benzamide;-   N-phenylcarbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;-   N-(4-bromophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;-   N-(4-methylphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;-   N-(4-methoxyphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl    ester;-   N-(3,4-dichlorophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl    ester;-   N-(4-cyanophenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;-   N-phenylcarbamic acid 1-azabicyclo[2.2.1]heptan-3-yl ester;-   N-(3-methoxyphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl    ester;-   N-phenylthiocarbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;-   N-(2-pyridyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;-   N-(1-naphthyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;-   N-phenylcarbamic acid (3R)-1-azabicyclo[2.2.2]octan-3-yl ester;-   N-phenylcarbamic acid (3S)-1-azabicyclo[2.2.2]octan-3-yl ester;-   N-(4-pyridyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;-   N-(m-biphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;-   N-(3-q uinolinyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl ester;-   N-(1-azabicyclo[2.2.2]oct-3-yl)(E-3-phenylpropenamide);-   N-(1-azabicyclo[2.2.2]oct-3-yl)(3-phenylpropenamide);    and pharmaceutically acceptable salts thereof.

Compounds useful according to the present invention also includecompounds of Formula 4:

In Formula 4, Ar is an aryl group, either carbocyclic or heterocyclic,either monocyclic or fused polycyclic, unsubstituted or substituted; Ris hydrogen, C₁-C₈ alkyl (e.g., straight chain or branched alkyl,preferably C₁-C₅, such as methyl, ethyl, or isopropyl), aryl, orarylalkyl (such as benzyl).

Such compounds are disclosed as α7 selective ligands in, for instance,PCTs WO 03/018585, WO 03/018586, WO 03/022856, WO 03/070732, WO03/072578, WO 04/039815 and WO 04/052348, and U.S. Pat. No. 6,562,816,each of which is incorporated herein in its entirety.

Particular embodiments according to the general Formula 4 include thefollowing:

-   N-(7-azabicyclo[2.2.1]hept-2-yl)-5-phenylthiophene-2-carbozamide;-   N-(7-azabicyclo[2.2.1]hept-2-yl)-5-(2-pyridinyl)thiophene-2-carbozamide;-   N-(7-azabicyclo[2.2.1]hept-2-yl)-5-phenylfuran-2-carbozamide;    and pharmaceutically acceptable salts thereof.

Compounds useful according to the present invention also includecompounds of Formula 5:

In Formula 5, n is 1 or 2; Ar is an aryl group, either carbocyclic orheterocyclic, either monocyclic or fused polycyclic, unsubstituted orsubstituted; and Z is oxygen, —CC—, —CH═CH— or a covalent bond.

Such compounds are disclosed as α7 selective ligands in, for instance,PCTs WO 00/058311, WO 04/016616, WO 04/016617, 04/061510, WO 04/061511and WO 04/076453, each of which is incorporated herein in its entirety.

Particular embodiments according to the general Formula 5 include thefollowing:

-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-methoxyphenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-chlorofuran-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-bromothiophen-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-phenoxyphenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-phenylfuran-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(3-pyridinyl)thiophen-2-yl)methanone;-   1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-phenylpropanone;    and pharmaceutically acceptable salts thereof.

Compounds useful according to the present invention also includecompounds of Formula 6:

In Formula 6, Ar is a fused polycyclic, heterocyclic aryl group,unsubstituted or substituted; and Z is —CH₂— or a covalent bond.

Such compounds are disclosed as α7 selective ligands in, for instance,PCTs WO 03/119837 and WO 05/111038 and U.S. Pat. No. 6,881,734, each ofwhich is herein incorporated by reference in its entirety.

Particular embodiments according to the general Formula 6 include thefollowing:

-   4-benzoxazol-2-yl-1,4-diazabicyclo[3.2.2.]nonane;-   4-benzothiazol-2-yl-1,4-diazabicyclo[3.2.2]nonane;-   4-benzoxazol-2-yl-1,4-diazabicyclo[3.2.2.]nonane;-   4-oxazolo[5,4-b]pyridine-2-yl-1,4-diazabicyclo[3.2.2.]nonane;-   4-(1H-benzimidazol-2-yl-1,4-diazabicyclo[3.2.2.]nonane;    and pharmaceutically acceptable salts thereof.

Compounds useful according to the present invention also includecompounds of Formula 7:

In Formula 7, Ar is an aryl group, either carbocyclic or heterocyclic,either monocyclic or fused polycyclic, unsubstituted or substituted; Xis either CH or N; Z is either oxygen, nitrogen (NR) or a covalent bond;and R is H or alkyl. Optionally, “Z—Ar” is absent from Formula 7.

Such compounds are disclosed as α7 selective ligands in, for instance,PCTs WO 00/042044, WO 02/096912, WO 03/087102, WO 03/087103, WO03/087104, WO 05/030778, WO 05/042538 and WO 05/066168, and U.S. Pat.No. 6,110,914, U.S. Pat. No. 6,369,224, U.S. Pat. No. 6,569,865, U.S.Pat. No. 6,703,502, U.S. Pat. No. 6,706,878, U.S. Pat. No. 6,995,167,U.S. Pat. No. 7,186,836 and U.S. Pat. No. 7,196,096, each of which isincorporated herein by reference in its entirety.

Particular embodiments according to the general Formula 7 include thefollowing:

-   spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];-   5′-phenylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];-   5′-(3-furanyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];-   5′-(2-thienyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];-   5′-(N-phenyl-N-methylamino)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];-   5′-(N-3-pyridinyl-N-methylamino)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];-   5′-(2-benzofuranyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];-   5′-(2-benzothiazolyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];-   5′-(3-pyridinyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];    and pharmaceutically acceptable salts thereof.

Compounds useful according to the present invention also includecompounds of Formula 8:

In Formula 8, Ar is an aryl group, either carbocyclic or heterocyclic,either unsubstituted or substituted.

Such compounds are disclosed as α7 selective ligands in, for instance,PCTs WO 05/005435 and WO 06/065209, each of which is herein incorporatedby reference in its entirety. Particular embodiments according to thegeneral Formula 8 include the following:

-   3′-(5-phenylthiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one;-   3′-(5-(3-pyridinyl)thiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one;    and pharmaceutically acceptable salts thereof.

Compounds useful according to the present invention also includecompounds of Formula 9:

In Formula 9, Ar is an aryl group, either carbocyclic or heterocyclic,either monocyclic or fused polycyclic, unsubstituted or substituted(preferably by aryl or aryloxy substituents).

Such compounds are disclosed as α7 selective ligands in, for instance,PCTs WO 04/016608, WO 05/066166, WO 05/066167, WO 07/018,738, and U.S.Pat. No. 7,160,876, each of which is herein incorporated by reference inits entirety.

Particular embodiments according to the general Formula 9 include thefollowing:

-   2-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole;-   3-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole;-   4-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole;-   5-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole;-   6-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1H-indole;-   5-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1H-indole;-   4-[6-(1-azabicyclo[2.2.2]oct-3-yloxy)pyridazin-3-yl]-1H-indole;-   5-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-3-methyl-1H-indazole;-   5-[2-(1-azabicyclo[2.2.2]oct-3-yloxy)pyrimidin-5-yl]-1H-indole;-   6-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)phenyl]-1,3-benzothiazol-3-amine;    and pharmaceutically acceptable salts thereof.

Compounds useful according to the present invention also includecompounds of Formula 10:

In Formula 10, Ar is an phenyl group, unsubstituted or substituted, andZ is either —CH═CH— or a covalent bond.

Such compounds are disclosed as α7 ligands in, for instance, PCTs WO92/15306, WO 94/05288, WO 99/10338, WO04/019943, WO 04/052365 and WO06/133303, and U.S. Pat. No. 5,741,802 and U.S. Pat. No. 5,977,144, eachof which is herein incorporated by reference in its entirety.

Particular embodiments according to the general Formula 10 include thefollowing:

-   3-(2,4-dimethoxybenzylidene)anabaseine;-   3-(4-hydroxybenzylidene)anabaseine;-   3-(4-methoxybenzylidene)anabaseine;-   3-(4-aminobenzylidene)anabaseine;-   3-(4-hydroxy-2-methoxybenzylidene)anabaseine;-   3-(2-hydroxy-4-methoxybenzylidene)anabaseine;-   3-(4-isopropoxybenzylidene)anabaseine;-   3-(4-acetylaminocinnamylidene)anabaseine;-   3-(4-hydroxycinnamylidene)anabaseine;-   3-(4-methoxycinnamylidene)anabaseine;-   3-(4-hydroxy-2-methoxycinnamylidene)anabaseine;-   3-(2,4-dimethoxycinnamylidene)anabaseine;-   3-(4-acetoxycinnamylidene)anabaseine;    and pharmaceutically acceptable salts thereof.

Compounds useful according to the present invention also includecompounds of Formula 11:

In Formula 11, n is 1 or 2; R is H or alkyl, but most preferably methyl;X is nitrogen or CH; Z is NH or a covalent bond, and when X is nitrogen,Z must be a covalent bond; and Ar is an indolyl, indazolyl,1,2-benzisoxazolyl or 1,2-benzisothiazolyl moiety, attached in each casevia the 3 position to the carbonyl.

Such compounds are disclosed as α7 ligands in, for instance, PCT WO06/001894, herein incorporated by reference in its entirety.

Particular embodiments according to the general Formula 11 include thefollowing:

-   (8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-6-(2-thienyl)-7H-indazole-3-carboxamide;-   3-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-7H-indazole;-   3-((8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl)-7H-indazole;-   5-methoxy-N-(9-methyl-9-azabicyclo[3.2.1]non-3-yl)-7H-indazole-3-carboxamide;-   6-methoxy-N-(9-methyl-9-azabicyclo[3.2.1]non-3-yl)-1,2-benzisothiazole-3-carboxamide;    and    pharmaceutically acceptable salts thereof.

SYNTHETIC EXAMPLES(2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanedi-p-toluoyl-D-tartrate salt

The following large scale synthesis of(2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanedi-p-toluoyl-D-tartrate salt is representative.

2-((3-Pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one

3-Quinuclidinone hydrochloride (8.25 kg, 51.0 mol) and methanol (49.5 L)were added to a 100 L glass reaction flask, under an nitrogenatmosphere, equipped with a mechanical stirrer, temperature probe, andcondenser. Potassium hydroxide (5.55 kg, 99.0 mol) was added via apowder funnel over an approximately 30 min period, resulting in a risein reaction temperature from 50° C. to 56° C. Over an approximately 2 hperiod, 3-pyridinecarboxaldehyde (4.80 kg, 44.9 mol) was added to thereaction mixture. The resulting mixture was stirred at 20° C.±5° C. fora minimum of 12 h, as the reaction was monitored by thin layerchromatography (TLC). Upon completion of the reaction, the reactionmixture was filtered through a sintered glass funnel and the filter cakewas washed with methanol (74.2 L). The filtrate was concentrated,transferred to a reaction flask, and water (66.0 L) was added. Thesuspension was stirred for a minimum of 30 min, filtered, and the filtercake was washed with water (90.0 L) until the pH of the rinse was 7-9.The solid was dried under vacuum at 50° C.±5° C. for a minimum of 12 hto give 8.58 kg (89.3%) of2-((3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one.

(2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-onedi-p-toluoyl-D-tartrate salt

2-((3-Pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (5.40 kg, 25.2mol) and methanol (40.5 L) were added to a 72 L reaction vessel under aninert atmosphere equipped with a mechanical stirrer, temperature probe,low-pressure gas regulator system, and pressure gauge. The headspace wasfilled with nitrogen, and the mixture was stirred to obtain a clearyellow solution. To the flask was added 10% palladium on carbon (50%wet) (270 g). The atmosphere of the reactor was evacuated using a vacuumpump, and the headspace was replaced with hydrogen to 10 to 20 incheswater pressure. The evacuation and pressurization with hydrogen wererepeated 2 more times, leaving the reactor under 20 inches waterpressure of hydrogen gas after the third pressurization. The reactionmixture was stirred at 20° C.±5° C. for a minimum of 12 h, and thereaction was monitored via TLC. Upon completion of the reaction, thesuspension was filtered through a bed of Celite®545 (1.9 kg) on asintered glass funnel, and the filter cake was washed with methanol(10.1 L). The filtrate was concentrated to obtain a semi-solid which wastransferred, under an nitrogen atmosphere, to a 200 L reaction flaskfitted with a mechanical stirrer, condenser, and temperature probe. Thesemi-solid was dissolved in ethanol (57.2 L), anddi-p-toluoyl-D-tartaric acid (DTTA) (9.74 kg, 25.2 mol) was added. Thestirring reaction mixture was heated at reflux for a minimum of 1 h, andfor an additional minimum of 12 h while the reaction was cooled tobetween 15° C. and 30° C. The suspension was filtered using a tabletopfilter, and the filter cake was washed with ethanol (11.4 L). Theproduct was dried under vacuum at ambient temperature to obtain 11.6 kg(76.2% yield, 59.5% factored for purity) of(2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-onedi-p-toluoyl-D-tartrate salt.

(2S,3R)-3-Amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanedi-p-toluoyl-D-tartrate salt

Water (46.25 L) and sodium bicarbonate (4.35 kg, 51.8 mol) were added toa 200 L flask. Upon complete dissolution, dichloromethane (69.4 L) wasadded. (2S)-2-((3-Pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-onedi-p-toluoyl-D-tartrate salt (11.56 kg, 19.19 mol) was added, and thereaction mixture was stirred for between 2 min and 10 min. The layerswere allowed to separate for a minimum of 2 min (additional water (20 L)was added when necessary to partition the layers). The organic phase wasremoved and dried over anhydrous sodium sulfate. Dichloromethane (34.7L) was added to the remaining aqueous phase, and the suspension wasstirred for between 2 min and 10 min. The layers were allowed toseparate for between 2 min and 10 min. Again, the organic phase wasremoved and dried over anhydrous sodium sulfate. The extraction of theaqueous phase with dichloromethane (34.7 L) was repeated one more time,as above. Samples of each extraction were submitted for chiral HPLCanalysis. The sodium sulfate was removed by filtration, and thefiltrates were concentrated to obtain(2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one (4.0 kg) asa solid.

The (2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one (3.8 kg)was transferred to a clean 100 L glass reaction flask, under a nitrogenatmosphere, fitted with a mechanical stirrer and temperature probe.Anhydrous tetrahydrofuran (7.24 L) and (+)-(R)-α-methylbenzylamine (2.55L, 20.1 mol) were added. Titanium(IV) isopropoxide (6.47 L, 21.8 mol)was added to the stirred reaction mixture over a 1 h period. Thereaction was stirred under a nitrogen atmosphere for a minimum of 12 h.Ethanol (36.17 L) was added to the reaction mixture. The reactionmixture was cooled to below −5° C., and sodium borohydride (1.53 kg,40.5 mol) was added in portions, keeping the reaction temperature below15° C. (this addition took several hours). The reaction mixture was thenstirred at 15° C.±10° C. for a minimum of 1 h. The reaction wasmonitored by HPLC, and upon completion of the reaction (as indicated byless than 0.5% of(2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one remaining),2 M sodium hydroxide (15.99 L) was added and the mixture was stirred fora minimum of 10 min. The reaction mixture was filtered through a bed ofCelite®545 in a tabletop funnel. The filter cake was washed with ethanol(15.23 L), and the filtrate was concentrated to obtain an oil.

The concentrate was transferred to a clean 100 L glass reaction flaskequipped with a mechanical stirrer and temperature probe under an inertatmosphere. Water (1 L) was added, and the mixture was cooled to 0°C.±5° C. 2 M Hydrochloric acid (24 L) was added to the mixture to adjustthe pH of the mixture to pH 1. The mixture was then stirred for aminimum of 10 min, and 2 M sodium hydroxide (24 L) was slowly added toadjust the pH of the mixture to pH 14. The mixture was stirred for aminimum of 10 min, and the aqueous phase was extracted withdichloromethane (3×15.23 L). The organic phases were dried overanhydrous sodium sulfate (2.0 kg), filtered, and concentrated to give(2S,3R)—N-((1R)-30phenylethyl)-3-amino-2-((3-pyridinyl)methyl))-1-azabicyclo[2.2.2]octane(4.80 kg, 84.7% yield).

The(2S,3R)—N-((1R)-phenylethyl)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanewas transferred to a 22 L glass flask equipped with a mechanical stirrerand temperature probe under an inert atmosphere. Water (4.8 L) wasadded, and the stirring mixture was cooled to 5° C.±5° C. Concentratedhydrochloric acid (2.97 L) was slowly added to the reaction flask,keeping the temperature of the mixture below 25° C. The resultingsolution was transferred to a 72 L reaction flask containing ethanol (18L), equipped with a mechanical stirrer, temperature probe, and condenserunder an inert atmosphere. To the flask was added 10% palladium oncarbon (50% wet) (311.1 g) and cyclohexene (14.36 L). The reactionmixture was heated at near-reflux for a minimum of 12 h, and thereaction was monitored by TLC. Upon completion of the reaction, thereaction mixture was cooled to below 45° C., and it was filtered througha bed of Celite®545 (1.2 kg) on a sintered glass funnel. The filter cakewas rinsed with ethanol (3 L) and the filtrate was concentrated toobtain an aqueous phase. Water (500 mL) was added to the concentratedfiltrate, and this combined aqueous layer was washed with methyltert-butyl ether (MTBE) (2×4.79 L). 2 M Sodium hydroxide (19.5 L) wasadded to the aqueous phase to adjust the pH of the mixture to pH 14. Themixture was then stirred for a minimum of 10 min. The aqueous phase wasextracted with chloroform (4×11.96 L), and the combined organic phaseswere dried over anhydrous sodium sulfate (2.34 kg). The filtrate wasfiltered and concentrated to obtain(2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (3.49kg, >quantitative yield) as an oil.

The (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanewas transferred to a clean 100 L reaction flask equipped with amechanical stirrer, condenser, and temperature probe under an inertatmosphere. Ethanol (38.4 L) and di-p-toluoyl-D-tartaric acid (3.58 kg,9.27 mol) were added. The reaction mixture was heated at gentle refluxfor a minimum of 1 h. The reaction mixture was then stirred for aminimum of 12 h while it was cooled to between 15° C. and 30° C. Theresulting suspension was filtered, and the filter cake was washed withethanol (5.76 L). The filter cake was transferred to a clean 100 L glassreaction flask equipped with a mechanical stirrer, temperature probe,and condenser under an inert atmosphere. A 9:1 ethanol/water solution(30.7 L) was added, and the resulting slurry was heated at gentle refluxfor a minimum of 1 h. The reaction mixture was then stirred for aminimum of 12 h while cooling to between 15° C. and 30° C. The mixturewas filtered and the filter cake was washed with ethanol (5.76 L). Theproduct was collected and dried under vacuum at 50° C.±5° C. for aminimum of 12 h to give 5.63 kg (58.1% yield) of(2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanedi-p-toluoyl-D-tartrate salt.

Compound A(2S,3R)—N-(2-((3-Pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)-5-methylthiophene-2-carboxamide

(2S,3R)-3-Amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanedi-p-toluoyl-D-tartrate salt (51.0 g, 84.5 mmol), water (125 mL), 2 Msodium hydroxide (150 mL) and chloroform (400 mL) were shaken togetherin a separatory funnel, and the chloroform layer was drawn off.

The aqueous layer was extracted three more times with chloroform (2×200mL, then 100 mL). The combined chloroform layers were washed withsaturated aqueous sodium chloride, dried over anhydrous sodium sulfateand concentrated by rotary evaporation. High vacuum treatment left(2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (18.0g) as an oil.

The (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanewas transferred to a 1 L glass reaction flask under an inert atmosphere.Dichloromethane (500 mL), triethylamine (40 mL, 0.30 mol),5-methylthiophene-2-carboxylic acid (13.5 g, 94.9 mmol) andO-(benzotriazol-1-yl)-N,N,N,1-tetramethyluronium hexafluorophosphate(HBTU) (36.0 g, 94.9 mmol) were added to the reaction mixture. Themixture was stirred overnight at ambient temperature, and at which timethe reaction was complete by HPLC. Water (200 mL), 2 M sodium hydroxide(200 mL) were added to the reaction, and the resulting mixture wasshaken. The dichloromethane layer and a 200 mL dichloromethane extractof the aqueous layer were combined and washed with saturated aqueoussodium chloride (200 mL), dried over anhydrous sodium sulfate andconcentrated, by rotary evaporation, to give an oil (quantitativeyield). Column chromatographic purification on silica gel, eluting witha methanol in ethyl acetate gradient, gave(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)-5-methylthiophene-2-carboxamide(22.6 g, 78.5% yield) as a powder.

Compound B(2S,3R)—N-(2-((3-Pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)-5-(2-pyridinyl)thiophene-2-carboxamide

A sample of(2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (5.5g, 25 mmol), generated as described above from(2S,3R)-3-Amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanedi-p-toluoyl-D-tartrate salt, was transferred to a 500 mL glass reactionflask under an inert atmosphere. Dichloromethane (200 mL), triethylamine(10 mL, 72 mmol), 5-(2-pyridinyl)thiophene-2-carboxylic acid (6.0 g, 29mmol) and O-(benzotriazol-1-yl)-N,N,N,1-tetramethyluroniumhexafluorophosphate (HBTU) (11.1 g, 29.2 mmol) were added to thereaction mixture. The mixture was stirred overnight at ambienttemperature, and at which time the reaction was complete by HPLC. Water(100 mL), 2 M sodium hydroxide (100 mL) were added to the reaction, andthe resulting mixture was shaken. The dichloromethane layer and two 250mL dichloromethane extracts of the aqueous layer were combined andwashed with saturated aqueous sodium chloride (200 mL), dried overanhydrous sodium sulfate and concentrated, by rotary evaporation, togive an oil (quantitative yield). Column chromatographic purification onsilica gel, eluting with a methanol in ethyl acetate gradient, gave(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)-5-(2-pyridinyl)thiophene-2-carboxamide(8.0 g, 80% yield) as a powder.

Compound C

(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)benzofuran-2-carboxamide

RacemicN-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide,a synthesis, and utility in medical treatment, is described in U.S. Pat.No. 6,953,855 to Mazurov et al, herein incorporated by reference.

Particular synthetic steps vary in their amenability to scale-up.Reactions are found lacking in their ability to be scaled-up for avariety of reasons, including safety concerns, reagent expense,difficult work-up or purification, reaction energetics (thermodynamicsor kinetics), and reaction yield. Both small scale and large scalesynthetic methods are herein described. The scalable synthesis utilizesboth the dynamic resolution of a racemizable ketone(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one) and thestereoselective reduction of the (R)-α-methylbenzylamine iminederivative (reductive amination) of the resolved ketone.

Small Scale 2-((3-Pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one

Potassium hydroxide (56 g, 0.54 mole) was dissolved in methanol (420mL). 3-Quinuclidinone hydrochloride (75 g, 0.49 mole) was added and themixture was stirred for 30 min at ambient temperature.3-Pyridinecarboxaldehyde (58 g, 0.54 mole) was added and the mixturestirred for 16 h at ambient temperature. The reaction mixture becameyellow during this period, with solids caking on the walls of the flask.The solids were scraped from the walls and the chunks broken up. Withrapid stirring, water (390 mL) was added. When the solids dissolved, themixture was cooled at 4° C. overnight. The crystals were collected byfiltration, washed with water, and air dried to obtain 80 g of yellowsolid. A second crop (8 g) was obtained by concentration of the filtrateto ˜10% of its former volume and cooling at 4° C. overnight. Both cropswere sufficiently pure for further transformation (88 g, 82% yield).

2-((3-Pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one

2-((3-Pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (20 g, 93mmol) was suspended in methanol (200 mL) and treated with 46 mL of 6 Mhydrochloric acid. 10% Palladium on carbon (1.6 g) was added and themixture was shaken under 25 psi hydrogen for 16 h. The mixture wasfiltered through diatomaceous earth, and the solvent was removed fromthe filtrate by rotary evaporation. This provided crude2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one hydrochloride, asa white gum (20 g), which was subsequently treated with 2 M sodiumhydroxide (50 mL) and chloroform (50 mL) and stirred for an hour. Thechloroform layer was separated, and the aqueous phase was treated with 2M sodium hydroxide (˜5 mL, enough to raise the pH to 10) and saturatedaqueous Sodium chloride (25 mL). This aqueous mixture was extracted withchloroform (3×10 mL), and the combined chloroform extracts were dried(anhydrous magnesium sulfate) and concentrated by rotary evaporation.The residue (18 g) was dissolved in warm ether (320 mL) and cooled to 4°C. The white solid was filtered off, washed with a small portion of coldether and air dried. Concentration of the filtrate to ˜10% of its formervolume and cooling at 4° C. produced a second crop. A combined yield 16g (79%) was obtained.

3-Amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane

To a stirred solution of2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one (3.00 g, 13.9mmol) in dry methanol (20 mL), under nitrogen, was added a 1 M solutionof zinc chloride in ether (2.78 mL, 2.78 mmol). After stirring atambient temperature for 30 min, this mixture was treated with solidammonium formate (10.4 g, 167 mmol). After stirring another hour atambient temperature, solid sodium cyanoborohydride (1.75 g, 27.8 mmol)was added in portions. The reaction was then stirred at ambienttemperature overnight and terminated by addition of water (˜5 mL). Thequenched reaction was partitioned between 5 M sodium hydroxide (10 mL)and chloroform (20 mL). The aqueous layer was extracted with chloroform(20 mL), and combined organic layers were dried (sodium sulfate),filtered and concentrated. This left 2.97 g of yellow gum. GCMS analysisindicated that the product was a 1:9 mixture of the cis and transamines, along with a trace of the corresponding alcohol (98% total massrecovery).

(2R,3S) and(2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane

Di-p-toluoyl-D-tartaric acid (5.33 g, 13.8 mmol) was added to a stirredsolution of crude3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (6.00 g, 27.6mmol of 1:9 cis/trans) in methanol (20 mL). After complete dissolution,the clear solution was then concentrated to a solid mass by rotaryevaporation. The solid was dissolved in a minimum amount of boilingmethanol (˜5 mL). The solution was cooled slowly, first to ambienttemperature (1 h), then for ˜4 h at 5° C. and finally at −5° C.overnight. The precipitated salt was collected by suction filtration andrecrystallized from 5 mL of methanol. Air drying left 1.4 g of whitesolid, which was partitioned between chloroform (5 mL) and 2 M sodiumhydroxide (5 mL). The chloroform layer and a 5 mL chloroform extract ofthe aqueous layer were combined, dried (anhydrous sodium sulfate) andconcentrated to give a colorless oil (0.434 g). The enantiomeric purityof this free base was determined by conversion of a portion into itsN-(tert-butoxycarbonyl)-L-prolinamide, which was then analyzed fordiastereomeric purity (98%) using LCMS.

The mother liquor from the initial crystallization was made basic (˜pH11) with 2 M sodium hydroxide and extracted twice with chloroform (10mL). The chloroform extracts were dried (anhydrous sodium sulfate) andconcentrated to give an oil. This amine (3.00 g, 13.8 mmol) wasdissolved in methanol (10 mL) and treated with di-p-toluoyl-L-tartaricacid (2.76 g, 6.90 mmol). The mixture was warmed to aid dissolution andthen cooled slowly to −5° C., where it remained overnight. Theprecipitate was collected by suction filtration, recrystallized frommethanol and dried. This left 1.05 g of white solid. The salt wasconverted into the free base (yield=0.364 g), and the enantiomericpurity (97%) was assessed using the prolinamide method, as describedabove for the other enantiomer.

Trans isomer 1 ofN-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)benzofuran-2-carboxamide

Diphenylchlorophosphate (0.35 mL, 0.46 g, 1.7 mmol) was added drop-wiseto a solution of benzofuran-2-carboxylic acid (0.28 g, 1.7 mmol) andtriethylamine (0.24 mL, 0.17 g, 1.7 mmol) in dry dichloromethane (5 mL).After stirring at ambient temperature for 30 min, a solution of(2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (0.337g, 1.55 mmol) (that derived from the di-p-toluoyl-D-tartaric acid salt)and triethylamine (0.24 mL, 0.17 g, 1.7 mmol) in dry dichloromethane (5mL) was added. The reaction mixture was stirred overnight at ambienttemperature, and then treated with 10% sodium hydroxide (1 mL). Thebiphasic mixture was separated, and the organic layer was concentratedon a Genevac centrifugal evaporator. The residue was dissolved inmethanol (6 mL) and purified by HPLC on a C18 silica gel column, usingan acetonitrile/water gradient, containing 0.05% trifluoroacetic acid,as eluent. Concentration of selected fractions, partitioning of theresulting residue between chloroform and saturated aqueous sodiumbicarbonate, and evaporation of the chloroform gave 0.310 g (42% yield)of white powder (95% pure by GCMS). ¹H NMR (300 MHz, CDCl₃) δ 8.51 (d,1H), 8.34 (dd, 1H), 7.66 (d, 1H), 7.58 (dt, 1H), 7.49 (d, 1H), 7.44 (s,1H), 7.40 (dd, 1H), 7.29 (t, 1H), 7.13 (dd, 1H), 6.63 (d, 1H), 3.95 (t,1H), 3.08 (m, 1H), 2.95 (m, 4H), 2.78 (m, 2H), 2.03 (m, 1H), 1.72 (m,3H), 1.52 (m, 1H). This material (trans enantiomer 1) was laterdetermined to be identical, by chiral chromatographic analysis, tomaterial whose absolute configuration is 2S,3R (established by x-raycrystallographic analysis).

Trans isomer 2 ofN-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)benzofuran-2-carboxamide

Diphenylchlorophosphate (96 μL, 124 mg, 0.46 mmol) was added drop-wiseto a solution of the benzofuran-2-carboxylic acid (75 mg, 0.46 mmol)(that derived from the di-p-toluoyl-L-tartaric acid salt) andtriethylamine (64 μL, 46 mg, 0.46 mmol) in dry dichloromethane (1 mL).After stirring at ambient temperature for 45 min, a solution of(2R,3S)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (0.10g, 0.46 mmol) and triethylamine (64 μL, 46 mg, 0.46 mmol) in drydichloromethane (1 mL) was added. The reaction mixture was stirredovernight at ambient temperature, and then treated with 10% sodiumhydroxide (1 mL). The biphasic mixture was separated, and the organiclayer and a chloroform extract (2 mL) of the aqueous layer wasconcentrated by rotary evaporation. The residue was dissolved inmethanol and purified by HPLC on a C18 silica gel column, using anacetonitrile/water gradient, containing 0.05% trifluoroacetic acid, aseluent. Concentration of selected fractions, partitioning of theresulting residue between chloroform and saturated aqueous sodiumbicarbonate, and evaporation of the chloroform gave 82.5 mg (50% yield)of a white powder. The NMR spectrum was identical to that obtained forthe (2S,3R) isomer. Since the immediate precursor of this material(trans enantiomer 2) is enantiomeric to the immediate precursor of 2S,3Rcompound (trans enantiomer 1), the absolute configuration of transenantiomer 2 is presumed to be 2R,3S.

Large Scale 2-((3-Pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one

3-Quinuclidinone hydrochloride (8.25 kg, 51.0 mol) and methanol (49.5 L)were added to a 100 L glass reaction flask, under an nitrogenatmosphere, equipped with a mechanical stirrer, temperature probe, andcondenser. Potassium hydroxide (5.55 kg, 99.0 mol) was added via apowder funnel over an approximately 30 min period, resulting in a risein reaction temperature from 50° C. to 56° C. Over an approximately 2 hperiod, 3-pyridinecarboxaldehyde (4.80 kg, 44.9 mol) was added to thereaction mixture. The resulting mixture was stirred at 20° C.±5° C. fora minimum of 12 h, as the reaction was monitored by thin layerchromatography (TLC). Upon completion of the reaction, the reactionmixture was filtered through a sintered glass funnel and the filter cakewas washed with methanol (74.2 L). The filtrate was concentrated,transferred to a reaction flask, and water (66.0 L) was added. Thesuspension was stirred for a minimum of 30 min, filtered, and the filtercake was washed with water (90.0 L) until the pH of the rinse was 7-9.The solid was dried under vacuum at 50° C.±5° C. for a minimum of 12 hto give 8.58 kg (89.3%) of2-((3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one.

(2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-onedi-p-toluoyl-D-tartrate salt

2-((3-Pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (5.40 kg, 25.2mol) and methanol (40.5 L) were added to a 72 L reaction vessel under aninert atmosphere equipped with a mechanical stirrer, temperature probe,low-pressure gas regulator system, and pressure gauge. The headspace wasfilled with nitrogen, and the mixture was stirred to obtain a clearyellow solution. To the flask was added 10% palladium on carbon (50%wet) (270 g). The atmosphere of the reactor was evacuated using a vacuumpump, and the headspace was replaced with hydrogen to 10 to 20 incheswater pressure. The evacuation and pressurization with hydrogen wererepeated 2 more times, leaving the reactor under 20 inches waterpressure of hydrogen gas after the third pressurization. The reactionmixture was stirred at 20° C.±5° C. for a minimum of 12 h, and thereaction was monitored via TLC. Upon completion of the reaction, thesuspension was filtered through a bed of Celite®545 (1.9 kg) on asintered glass funnel, and the filter cake was washed with methanol(10.1 L). The filtrate was concentrated to obtain a semi-solid which wastransferred, under an nitrogen atmosphere, to a 200 L reaction flaskfitted with a mechanical stirrer, condenser, and temperature probe. Thesemi-solid was dissolved in ethanol (57.2 L), anddi-p-toluoyl-D-tartaric acid (DTTA) (9.74 kg, 25.2 mol) was added. Thestirring reaction mixture was heated at reflux for a minimum of 1 h, andfor an additional minimum of 12 h while the reaction was cooled tobetween 15° C. and 30° C. The suspension was filtered using a tabletopfilter, and the filter cake was washed with ethanol (11.4 L). Theproduct was dried under vacuum at ambient temperature to obtain 11.6 kg(76.2% yield, 59.5% factored for purity) of(2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-onedi-p-toluoyl-D-tartrate salt.

(2S,3R)-3-Amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanedi-p-toluoyl-D-tartrate salt

Water (46.25 L) and sodium bicarbonate (4.35 kg, 51.8 mol) were added toa 200 L flask. Upon complete dissolution, dichloromethane (69.4 L) wasadded. (2S)-2-((3-Pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-onedi-p-toluoyl-D-tartrate salt (11.56 kg, 19.19 mol) was added, and thereaction mixture was stirred for between 2 min and 10 min. The layerswere allowed to separate for a minimum of 2 min (additional water (20 L)was added when necessary to partition the layers). The organic phase wasremoved and dried over anhydrous sodium sulfate. Dichloromethane (34.7L) was added to the remaining aqueous phase, and the suspension wasstirred for between 2 min and 10 min. The layers were allowed toseparate for between 2 min and 10 min. Again, the organic phase wasremoved and dried over anhydrous sodium sulfate. The extraction of theaqueous phase with dichloromethane (34.7 L) was repeated one more time,as above. Samples of each extraction were submitted for chiral HPLCanalysis. The sodium sulfate was removed by filtration, and thefiltrates were concentrated to obtain(2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one (4.0 kg) asa solid.

The (2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one (3.8 kg)was transferred to a clean 100 L glass reaction flask, under a nitrogenatmosphere, fitted with a mechanical stirrer and temperature probe.Anhydrous tetrahydrofuran (7.24 L) and (+)-(R)-α-methylbenzylamine (2.55L, 20.1 mol) were added. Titanium(IV) isopropoxide (6.47 L, 21.8 mol)was added to the stirred reaction mixture over a 1 h period. Thereaction was stirred under a nitrogen atmosphere for a minimum of 12 h.Ethanol (36.17 L) was added to the reaction mixture. The reactionmixture was cooled to below −5° C., and sodium borohydride (1.53 kg,40.5 mol) was added in portions, keeping the reaction temperature below15° C. (this addition took several hours). The reaction mixture was thenstirred at 15° C.±10° C. for a minimum of 1 h. The reaction wasmonitored by HPLC, and upon completion of the reaction (as indicated byless than 0.5% of(2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one remaining),2 M sodium hydroxide (15.99 L) was added and the mixture was stirred fora minimum of 10 min. The reaction mixture was filtered through a bed ofCelite®545 in a tabletop funnel. The filter cake was washed with ethanol(15.23 L), and the filtrate was concentrated to obtain an oil.

The concentrate was transferred to a clean 100 L glass reaction flaskequipped with a mechanical stirrer and temperature probe under an inertatmosphere. Water (1 L) was added, and the mixture was cooled to 0°C.±5° C. 2 M Hydrochloric acid (24 L) was added to the mixture to adjustthe pH of the mixture to pH 1. The mixture was then stirred for aminimum of 10 min, and 2 M sodium hydroxide (24 L) was slowly added toadjust the pH of the mixture to pH 14. The mixture was stirred for aminimum of 10 min, and the aqueous phase was extracted withdichloromethane (3×15.23 L). The organic phases were dried overanhydrous sodium sulfate (2.0 kg), filtered, and concentrated to give(2S,3R)—N-((1R)-phenylethyl)-3-amino-2-((3-pyridinyl)methyl))-1-azabicyclo[2.2.2]octane(4.80 kg, 84.7% yield).

The(2S,3R)—N-((1R)-phenylethyl)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanewas transferred to a 22 L glass flask equipped with a mechanical stirrerand temperature probe under an inert atmosphere. Water (4.8 L) wasadded, and the stirring mixture was cooled to 5° C.±5° C. Concentratedhydrochloric acid (2.97 L) was slowly added to the reaction flask,keeping the temperature of the mixture below 25° C. The resultingsolution was transferred to a 72 L reaction flask containing ethanol (18L), equipped with a mechanical stirrer, temperature probe, and condenserunder an inert atmosphere. To the flask was added 10% palladium oncarbon (50% wet) (311.1 g) and cyclohexene (14.36 L).

The reaction mixture was heated at near-reflux for a minimum of 12 h,and the reaction was monitored by TLC. Upon completion of the reaction,the reaction mixture was cooled to below 45° C., and it was filteredthrough a bed of Celite®545 (1.2 kg) on a sintered glass funnel. Thefilter cake was rinsed with ethanol (3 L) and the filtrate wasconcentrated to obtain an aqueous phase. Water (500 mL) was added to theconcentrated filtrate, and this combined aqueous layer was washed withmethyl tert-butyl ether (MTBE) (2×4.79 L). 2 M Sodium hydroxide (19.5 L)was added to the aqueous phase to adjust the pH of the mixture to pH 14.The mixture was then stirred for a minimum of 10 min. The aqueous phasewas extracted with chloroform (4×11.96 L), and the combined organicphases were dried over anhydrous sodium sulfate (2.34 kg). The filtratewas filtered and concentrated to obtain(2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (3.49kg, >quantitative yield) as an oil.

The (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanewas transferred to a clean 100 L reaction flask equipped with amechanical stirrer, condenser, and temperature probe under an inertatmosphere. Ethanol (38.4 L) and di-p-toluoyl-D-tartaric acid (3.58 kg,9.27 mol) were added. The reaction mixture was heated at gentle refluxfor a minimum of 1 h. The reaction mixture was then stirred for aminimum of 12 h while it was cooled to between 15° C. and 30° C. Theresulting suspension was filtered, and the filter cake was washed withethanol (5.76 L). The filter cake was transferred to a clean 100 L glassreaction flask equipped with a mechanical stirrer, temperature probe,and condenser under an inert atmosphere. A 9:1 ethanol/water solution(30.7 L) was added, and the resulting slurry was heated at gentle refluxfor a minimum of 1 h. The reaction mixture was then stirred for aminimum of 12 h while cooling to between 15° C. and 30° C. The mixturewas filtered and the filter cake was washed with ethanol (5.76 L). Theproduct was collected and dried under vacuum at 50° C.±5° C. for aminimum of 12 h to give 5.63 kg (58.1% yield) of(2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanedi-p-toluoyl-D-tartrate salt.

(2S,3R)—N-(2-((3-Pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)benzofuran-2-carboxamide

(2S,3R)-3-Amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanedi-p-toluoyl-D-tartrate salt (3.64 kg, 5.96 mol) and 10% aqueous sodiumchloride solution (14.4 L, 46.4 mol) were added to a 72 L glass reactionflask equipped with a mechanical stirrer under an inert atmosphere. 5 MSodium hydroxide (5.09 L) was added to the stirring mixture to adjustthe pH of the mixture to pH 14. The mixture was then stirred for aminimum of 10 min. The aqueous solution was extracted with chloroform(4×12.0 L), and the combined organic layers were dried over anhydroussodium sulfate (1.72 kg). The combined organic layers were filtered, andthe filtrate was concentrated to obtain(2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (1.27kg) as an oil.

The (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octanewas transferred to a 50 L glass reaction flask equipped with amechanical stirrer under an inert atmosphere. Dichloromethane (16.5 L),triethylamine (847 mL, 6.08 mol), benzofuran-2-carboxylic acid (948 g,5.85 mol) and O-(benzotriazol-1-yl)-N,N,N,1-tetramethyluroniumhexafluorophosphate (HBTU) (2.17 kg, 5.85 mol) were added to thereaction mixture. The mixture was stirred for a minimum of 4 h atambient temperature, and the reaction was monitored by HPLC. Uponcompletion of the reaction, 10% aqueous potassium carbonate (12.7 L,17.1 mol) was added to the reaction mixture and the mixture was stirredfor a minimum of 5 min. The layers were separated and the organic phasewas washed with 10% brine (12.7 L). The layers were separated and theorganic phase was cooled to 15° C.±10° C. 3 M Hydrochloric acid (8.0 L)was slowly added to the reaction mixture to adjust the pH of the mixtureto pH 1. The mixture was then stirred for a minimum of 5 min, and thelayers were allowed to partition for a minimum of 5 min. The solids werefiltered using a table top filter. The layers of the filtrate wereseparated, and the aqueous phase and the solids from the funnel weretransferred to the reaction flask. 3 M Sodium hydroxide (9.0 L) wasslowly added to the flask in portions to adjust the pH of the mixture topH 14. The aqueous phase was extracted with dichloromethane (2×16.5 L).The combined organic phases were dried over anhydrous sodium sulfate(1.71 kg). The mixture was filtered, and the filtrate was concentratedto give(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)benzofuran-2-carboxamide(1.63 kg, 77.0% yield) as a yellow solid.

(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl]benzofuran-2-carboxamide13-toluenesulfonate

(2S,3R)—N-(2-((3-Pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)benzofuran-2-carboxamide(1.62 kg, 4.48 mol) and dichloromethane (8.60 kg) were added into acarboy. The weight/weight percent of the material in solution wasdetermined through HPLC analysis. The solution was concentrated to anoil, acetone (4 L) was added, and the mixture was concentrated to anoily solid. Additional acetone (12 L) was added to the oily solid in therotary evaporator bulb, and the resulting slurry was transferred to a 50L glass reaction flask with a mechanical stirrer, condenser, temperatureprobe, and condenser under an inert atmosphere. The reaction mixture washeated to 50° C.±5° C. Water (80.7 g) was added to the solution, and itwas stirred for a minimum of 10 min. p-Toluenesulfonic acid (853 g, 4.44mol) was added to the reaction mixture in portions over approximately 15min. The reaction mixture was heated to reflux and held at thattemperature for a minimum of 30 min to obtain a solution. The reactionwas cooled to 40° C.±5° C. over approximately 2 h. Isopropyl acetate(14.1 L) was added over approximately 1.5 h. The reaction mixture wasslowly cooled to ambient temperature over a minimum of 10 h. The mixturewas filtered and the filter cake was washed with isopropyl acetate (3.5L). The isolated product was dried under vacuum at 105° C.±5° C. forbetween 2 h and 9 h to give 2.19 kg (88.5% yield) of(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamidep-toluenesulfonate, mp 226-228° C. ¹H NMR (500 MHz, D₂O) δ 8.29 (s, 1H),7.78 (m, J=5.1, 1H), 7.63 (d, J=7.9, 1H), 7.54 (d, J=7.8, 1H), 7.49 (d,J=8.1, 2H), 7.37 (m, J=8.3, 1H), 7.33 (m, J=8.3, 6.9, 1.0, 1H), 7.18 (m,J=7.8, 6.9, 1.0, 1H), 7.14 (d, J=8.1, 2H), 7.09 (s, 1H), 6.99 (dd,J=7.9, 5.1, 1H), 4.05 (m, J=7.7, 1H), 3.74 (m, 1H), 3.47 (m, 2H), 3.28(m, 1H), 3.22 (m, 1H), 3.15 (dd, J=13.2, 4.7, 1H), 3.02 (dd, J=13.2,11.5, 1H), 2.19 (s, 3H), 2.02 (m, 2H), 1.93 (m, 2H), 1.79 (m, 1H). ¹³CNMR (126 MHz, D₂O) δ 157.2, 154.1, 150.1, 148.2, 146.4, 145.2, 138.0,137.0, 130.9, 128.2 (2), 126.9, 126.8, 125.5 (2), 123.7, 123.3, 122.7,111.7, 100.7, 61.3, 50.2, 48.0, 40.9, 33.1, 26.9, 21.5, 20.8, 17.0.

Samples of this material were converted into Compound C free base (foruse in salt selection studies) by treatment with aqueous sodiumhydroxide and extraction with chloroform. Thorough evaporation of thechloroform left an off-white powder, mp 167-170° C., with the followingspectral characteristics: Positive ion electrospray MS [M+H]⁺ ionm/z=362. ¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (d, J=7.6 Hz, 1H), 8.43 (d,J=1.7 Hz, 1H), 8.28 (dd, J=1.6, 4.7 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H),7.66 (d, J=8.5 Hz, 1H), 7.63 (dt, J=1.7, 7.7 Hz, 1H), 7.52 (s, 1H), 7.46(m, J=8.5, 7.5 Hz, 1H), 7.33 (m, J=7.7, 7.5 Hz, 1H), 7.21 (dd, J=4.7,7.7 Hz, 1H), 3.71 (m, J=7.6 Hz, 1H), 3.11 (m, 1H), 3.02 (m, 1H), 2.80(m, 2H), 2.69 (m, 2H), 2.55 (m, 1H), 1.80 (m, 1H), 1.77 (m, 1H), 1.62(m, 1H), 1.56 (m, 1H), 1.26 (m, 1H). ¹³C NMR (126 MHz, DMSO-d₆) δ 158.1,154.1, 150.1, 149.1, 146.8, 136.4, 135.4, 127.1, 126.7, 123.6, 122.9,122.6, 111.8, 109.3, 61.9, 53.4, 49.9, 40.3, 35.0, 28.1, 26.1, 19.6.

The monohydrochloride salt of Compound C (see Example 5) was submittedfor x-ray crystallographic analysis. The resulting crystal structureestablished the 2S,3R absolute configuration of Compound C.

Example 5 Synthesis of(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamidehydrochloride salt

A hydrochloric acid/THF solution was prepared by adding of concentratedhydrochloric acid (1.93 mL of 12M, 23.2 mmol) drop-wise to 8.5 mL ofchilled THF. The solution was warmed to ambient temperature. To a roundbottom flask was added(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide(8.49 g, 23.5 mmol) and acetone (85 mL). The mixture was stirred andheated at 45-50° C. until a complete solution was obtained. Thehydrochloric acid/THF solution prepared above was added drop-wise over a5 min period, with additional THF (1.5 mL) used in the transfer.Granular, white solids began to form during the addition of the acidsolution. The mixture was cooled to ambient temperature, and stirredovernight (16 h). The solids were collected by suction filtration, thefilter cake was washed with acetone (10 mL), and the solid was air-driedwith suction for 30 min. The solid was further dried in a vacuum oven at75° C. for 2 h to give 8.79 g of the fine white crystals (94% yield), mp255-262° C. Chiral LC analysis gave a purity of 98.8% (270 nm). ¹H-NMR(DMSO-d₆) shows no residual solvents and confirms mono stoichiometry. ¹HNMR (300 MHz, DMSO-d₆) δ 10.7 (broad s, 1H—quaternary ammonium), 8.80(broad s, 1H—amide H), 8.54 (s, 1H), 8.23 (d, 1H), 7.78 (d, 1H), 7.74(d, 1H), 7.60 (d, 1H), 7.47 (m, 2H), 7.33 (m, 1H), 7.19 (m, 1H), 4.19(m, 1H), 4.08 (m, 1H), 3.05-3.55 (m, 6H), 2.00-2.10 (m, 3H), 1.90 (m,1H), 1.70 (m, 1H). An x-ray crystallographic analysis of this saltestablished stereochemical assignment and stoichiometry.

Biological Examples

Compounds A, B, and C are α7-selective ligands. For example, CompoundsA, B and C are α7 agonists with Ki values=1-2 nM in displacement studiesusing ³H-MLA in rat hippocampal tissues. These compounds exhibit verypoor affinity at other nicotinic receptors, namely >1000 nM, includingα4β2. In functional studies, Compounds A, B and C exhibited E_(max)values >50% in an electrophysiology functional assay in Xenopus laevisoocytes transiently expressing human α7 nicotinic receptor. The IC50sfor Compound A are >10 micromolar at more than 60 targets in a receptorprofile screen.

Physiological Effects of Selective Alpha7 nAChR Agonist

Body Weight Gain and Food Intake. Several protein tyrosine phosphatases(PTPases) such as PTP1B, LAR, SHP-2 and PTEN have been implicated in thedevelopment of insulin resistance. In the present studies we measuredbody mass and weight gain in lean (db+) and obese (db−) mice that wereeither wild type (PTP1B+) or knockout (PTP1B−) for the proteinphosphatase 1B gene, following treatment with an α7 nAChR agonist,Compound A, B, or C.

At the end of seven weeks of treatment we found that weight gain wasreduced in the alpha7 agonist-treated ten week old db− mice. The db+lean mice were unaffected by treatment, confirming that the compound wasnot producing toxic effects that limited food intake. The weight gain incontrol obese groups (db−) was significantly lower (p<0.01) than that ofcontrols in both the PTP1B wild type and PTP1B knockout mice. Inaddition, the daily food intake was significantly lower (p<0.01) in thetreated mice than in the controls, in both PTP1B wild type and knockoutmice.

When the alpha7 antagonist, MLA, was given concurrently, the obese miceshowed no significant differences in body weight gain or food intake. Assuch, dietary supplementation with treatment compound effectivelylowered food intake and weight gain in obese mice. α7 nAChRs play acentral role in regulating food intake through a mechanism that is notdependent on PTP1B. Further, AG-490 significantly inhibited (p<0.01)both the weight loss and decreased food intake induced by the α7agonist.

Glucose Metabolism. Similar to the results obtained for food intake andbody weight gain, at the end of seven weeks of treatment, plasma glucoselevels in the obese (db−) mice treated with the α7 agonist weresignificantly lower (p<0.01) than those in the untreated PTP1B+ andPTP1B− mice. The α7 nAChR antagonist MLA was given concurrently withtreatment compound and the mice showed no significant decrease in plasmaglucose.

Dietary supplementation with the α7 agonist, therefore, effectivelylowers weight gain and food intake in obese mice and lowers theincreased levels of glucose due to obesity. This mechanism is notdependent on PTP1B, but rather on JAK2 activation. The JAK2 inhibitorsignificantly prevented (p<0.01) the treatment-induced decrease inplasma glucose. Lean mice displayed rapid glucose disposal and theinjected bolus was cleared within 30 minutes. Clearance of glucose inthe lean mice treated was similar to that of sham-treated mice.Consistent with obesity-induced insulin resistance, the obese miceshowed markedly blunted glucose clearance, removing only 50% of theinjected bolus within 30 minutes. By contrast, the treated mice showednormalization of glucose clearance despite obesity (90% of the injectedbolus within 30 minutes. Thus, insulin resistance is improved by thealpha7 agonist because in the presence of the α7 antagonist MLA theincreased insulin sensitivity is abrogated.

Glycosylation of Hemoglobin. Total glycemic load reflects both fastingand post-prandial glucose levels in the blood. A time averaged index ofglycemic load is accumulation of advanced glycation end products (AGEs),which can be estimated from the glycosylation of hemoglobin, HbA1c. Leantreated and non-treated PTP1B+ and PTP1B− mice all showed HbA1C levelslower than 5%, consistent with normal glycemic control. In contrast,obese mice showed markedly elevated HbA1c levels, consistent with theobserved glucose intolerance fasting hyperglycemia, which weresignificantly lowered (p<0.01) by the α7 agonist. In the PTP1B knockoutmice, HbA1c levels were markedly reduced and further reduced bytreatment. α7 nAChR plays a central role in regulating both the fastingand post-prandial glucose levels in the blood and that this effect isnot dependent on PTP1B. In the presence of the α7 antagonist, MLA, theincreased insulin sensitivity induced by the α7 agonist is suppressed.

Lipid Metabolism. Treated and non-treated lean mice show normal levelsof triglycerides. However, obese mice display elevated fastingtriglyceride levels, consistent with the loss of insulin sensitivity infat cells. Nevertheless, when the obese mice were treated they displayedlargely normal levels of triglycerides, an effect which was blocked bythe α7 antagonist MLA, suggesting a normalization of adipocyte insulinresistance via an α7 nAChR-mediated pathway.

Plasma TNF-α Levels. Plasma concentration of inflammatory mediators suchas TNF-α is increased in the insulin resistant states of obesity andtype 2 diabetes. Reduction of the levels of TNFα in diabetic micecorrelates with increased insulin sensitivity and decreased plasmainsulin and blood glucose levels. Treated and non-treated lean miceshowed no change in the plasma levels of TNF-α, but obese mice hadelevated fasting plasma TNF-α levels. However, when the obese mice weretreated, they displayed significantly decreased plasma TNF-α levels andthis was blocked by the α7 antagonist MLA, confirming that α7 nAChRs aredirectly involved in blocking the obesity-induced increase of TNF-α andhence the decreased insulin resistance.

α7 agonist on Obesity. Animal Models: Parental strains of mice used inthese studies were the leptin receptor deficient db/db mice on a C57BL6background obtained from Jackson Laboratories and PTP1B-null mice on amixed C57BL6/Balb C background from Dr. Michel Tremblay at the CancerInstitute at McGill University in Montreal, Canada. Because obese db/dbmice are infertile, mice were generated as dual heterozygotes,heterozygous for both the mutant leptin receptor and the deleted PTP1B.Dual heterozygotes were interbred, producing 1:4 obese mice and 1:4PTP-1B null mice. In this breeding configuration 1:16 were dual KO mice.In the fourth generation, mice heterozygous for both genes were bred toPTP-1B null mice heterozygous for the mutant db allele. In this breedingconfiguration 1:4 mice were obese and 1:8 were dual KO mice. For reasonsof parsimony, heterozygotes were preferred to wild-types over controls.Dual heterozygous littermates were used as lean controls and littermatesheterozygous for db were used as lean PTP1B KO controls.

Mouse genotyping: At 3 weeks of age, DNA was obtained by tail clip. Thegenomic DNA from tail clip was used to screen for the presence of themutant leptin receptor and deletion cassette of PTP-1B using thePolymerase Chain Reaction. Specific genotypes were determining byresolving PCR products with agarose gel electrophoresis. Deletion ofPTP-1B was verified by Western analysis using an anti-PTP-1B antibodyfrom Upstate Biotechnology.

Metabolic Phenotyping: The effects of the tested compound (for example,Compound A at 1 mg/kg/day via oral gavage) on growth rates and foodintake of mice were generated by measuring body weight and food intakebi-weekly for from ages 3 to 10 weeks. In selected cohorts, the α7antagonist MLA was also given via gavage, concurrently, at 3 mg/kgdaily. The JAK2 kinase inhibitor (AG-490) was administeredintraperitoneally (IP) at 1 mg/kg daily. Fasting glucose was measuredonce a week after food withdrawal, with a Precision XL glucometer usingtail vein bleeding. HbA1c levels were also measured from these sampleswith the A1C kit from Metrika, Inc. To assess glucose tolerance, themice were anesthetized with 2% isoflurane and the left carotid arteryand jugular vein cannulated after an overnight fast. A 10 mg bolus ofglucose was injected intravenously (iv) via the jugular vein and bloodglucose measured every 5 minutes for 40 minutes in a drop of blood fromthe carotid line. For measurements of blood plasma analytes, a separategroup of fasted mice were anesthetized by isoflurane in a rapidinduction chamber and swiftly decapitated. Blood was collected inheparin and rapidly centrifuged at 4° C. to remove cells and to obtainplasma, and the samples were frozen for later analyses. Plasma TNF-αconcentrations were determined using ELISA assay kits from eBioscienceand plasma triglyceride levels were determined using the L-Type TG Htest (Wako Diagnostics), an in vitro assay for the quantitativedetermination of triglycerides in serum or plasma. All data areexpressed as mean and SEM. Differences among all groups were compared byOne Way ANOVA.

Statistics: All data are expressed as mean and SEM. Differences amongall four genotypes were compared by One Way ANOVA.

Effects of an α7 Selective Ligand on STZ-Induced Diabetes.

The effects of an α7 selective ligand on the STZ-induced diabetes andthe influence of JAK2: In order to induce diabetes in the mice fivemultiple doses of STZ (50 mg/kg ip) or vehicle (citrate buffer) wereadministered daily for ten days as suggested for such investigations.Mice were weighed and blood glucose levels were determined at baselineand every four days thereafter. The mice reached stable hyperglycemiawithin two weeks. Now in order to determine the influence of JAK2,conditional floxed JAK2 KO mice provided by Dr. Wagner were used. Thesemice were crossed with inducible non-tissue specific mER-Cre mice fromJackson Labs. These mER-Cre mutant mice have an inducible element whichis a mERT2-Cre fusion cDNA, which encodes the mutated murine estrogenreceptor ligand-binding domain (amino acids 281 to 599, G525R) and whichis insensitive to estrogen but sensitive to tamoxifen. This inducibletransgenic mouse line facilitates gene targeting and would be beneficialin investigating the role of JAK2 in the adult mouse. The time point ofCre activity can be regulated by injections with tamoxifen and usingthese inducible Cre transgenic mice, we will be able to generate JAK2 KOmutants in a conditional and inducible manner. Homozygous JAK2flox micecarrying the mCre/mERT (i.e., mER-Cre/JAK2flox) were generated bybreeding double heterozygous mice containing JAK2flox and Cre/mERT, andhave assess the efficiency of induced Cre-mediated deletion of the loxPflanked JAK2 gene segment via Southern assay before and afterintraperitoneal injections of tamoxifen. Western blot analysisdemonstrates that after 7 days of intraperitoneal injections oftamoxifen at a concentration of 20 mg/kg there was a total ablation ofJAK2 expression in the pancreas while there is no effect on theexpression of Actin. In addition, analysis of mouse growth by bodyweight (age 1 to 16 weeks) prior to or after tamoxifen administrationshowed no differences among the genotypes. Furthermore, themER-Cre/JAK2flox mice had grossly normal appearance, activity andbehavior. Two separate groups of mER-Cre/JAK2+/+ and mER-Cre-JAK2floxadult mice (age, 7 weeks), post tamoxifen treatment, were then madediabetic as described above with five multiple low doses of STZ everyother day with or without the compound, for example Compound A (1mg/kg/day via oral gavage). All the groups of mice (i.e.,mER-Cre/JAK2+/+ and mER-Cre-JAK2flox) reached stable hyperglycemiawithin two weeks.

The effects of tested compound on STZ-induced diabetes and cytokineslevels were measured via the following ways. For example, fastingglucose levels were measured at least twice a week via tail veinbleeding with a Precision XL glucometer while HbA1c levels were measuredusing the A1C kit from Metrika Inc. In a second group of mice, fastedmice were anesthetized by isofluorance in a rapid induction chamber andswiftly decapitated. Trunk blood was collected in heparin and rapidlycentrifuged at 4C to remove blood cells and obtain plasma. Samples werefrozen for later analyses. Plasma insulin, TNFα and IL-6 concentrationwere determined using ELISA assay kits.

Statistics: All data are expressed as mean and SEM. Differences amongall four genotypes were compared by One Way ANOVA.

Animal Models and Metabolic Phenotyping: Parental strains of mice usedin these studies were the leptin receptor deficient db/db fat mice orleptin receptor wild type DB/DB lean mice on a C57BL6 backgroundobtained from Jackson Laboratories. Animal were treated with simvastatinand tested compound, such as Compound A at 1 mg/kg/day via gavage.Growth rates of mice were generated by measuring body weight twiceweekly for 10 weeks. Daily food intake was measured in mice metaboliccages obtained from Fisher. To assess glucose tolerance, mice wereanesthetized with 2% isoflurane and the left carotid artery and jugularvein cannulated after an overnite fast. Fasting blood glucose wasassessed as the initial two measurements in the anesthetized mice. Asecond measurement was used to determine HbA1c levels using the A1CNowkit from Metrika Inc. A 10 mg bolus of glucose was injected into eachmouse and blood glucose measure by a drop of blood from the carotid lineevery 5 minutes for 40 minutes. Glucose was measured with a Precision XLglucometer. At the end of the experiment mice were euthanized byisoflurane overdose. In a second group of mice, fasted mice wereanesthetized by isofluorance in a rapid induction chamber and swiftlydecapitated. Trunk blood was collected in heparin and rapidlycentrifuged to remove blood cells and obtain plasma. Samples were thencollected for analyses. Plasma cholesterol, free fatty acids andtriglycerides were determined using colorimetric assays from WakoChemical while plasma TNFα concentration was determined using ELISAassay kits from eBioscience.

These data indicate that Compounds A, B, and C ameliorate glycemic statein type II diabetes.

The compounds, Compounds A, B, and C, are demonstrated to reduce weightgain, normalize glucose levels, decrease glycated hemoglobin, reducepro-inflammatory cytokines, reduce triglycerides, and normalize insulinresistance glucose tolerance test. These data indicate that α7 ligands,including Compounds A, B, and C, ameliorate the glycemic state inmetabolic disorders such as diabetes type II and biological parametersassociated with the metabolic syndrome.

Selective α7 nAChR agonists can reduce weight gain, normalize glucoselevels, decrease glycated hemoglobin, reduce the pro-inflammatorycytokine TNF-α, reduce triglycerides, and normalize insulin sensitivityin transgenic models of type 2 diabetes. These effects were notprevented in obese mice lacking the phosphotyrosine phosphatase PTP1Bbut were fully reversed by the α7 antagonist MLA. Furthermore, the JAK2kinase specific inhibitor AG-490 also inhibited the α7 agonist-inducedweight loss, decreased food intake and normalization of glucose levels.α7 nAChRs play a central role in regulating the biological parametersassociated with type 2 diabetes and the metabolic syndrome.

Insulin resistance, diabetes, obesity and dyslipidemia are components ofthe metabolic syndrome, and although pro-inflammatory cytokines havebeen suggested to contribute to the development of these disorders, themolecular mechanism of the development of this syndrome is poorlyunderstood. The CNS modulates the immune system through thereticuloendothelial system. This CNS modulation is mediated through thevagus nerve, utilizing the major vagal neurotransmitter acetylcholinewhich acts upon α7 nAChRs on macrophages. Neuroprotective effectselicited by α7-selective ligands can be traced to α7 nAChR activationand transduction of signals to PI-3-K (phosphatidylinositol 3-kinase)and AKT (protein kinase B) through the protein tyrosine kinase Januskinase 2 (JAK2), all of which compose a key cell survival pathway. Theresults of co-immunoprecipitation experiments indicate that there is adirect interaction between the alpha7 nicotinic receptor and JAK2. Otherstudies that examined the effects of nicotine on LPS-treated and controlperitoneal macrophages have shown that nicotine treatment leads tophosphorylation of STAT3, a member of the STAT (Signal transducers andactivators of transcription) family of proteins and a component of thecellular anti-apoptotic cascade. This nicotine-mediated phosphorylationis inhibited by the α7-selective antagonists α-bungarotoxin and MLA, andby AG-490, a selective inhibitor of JAK2 phosphorylation. These datasupport the interaction of JAK2 and α7 nAChRs and reveal the criticalrole played by STAT3 in the cholinergic anti-inflammatory pathway. Thepresent results extend these findings and underline the importance of α7nAChR interactions with JAK2 in modulating the biological parametersassociated with weight gain and food intake. Interestingly, regulatoryfeedback on adiposity, mediated by the leptin receptor in hypothalamus,also involves receptor-JAK2 interactions. In obese mice which lack anactive leptin receptor (i.e., db/db mice) the α7 nAChR may substitutefor the leptin receptor in the activation of JAK2, which in turn leadsto decreased food intake and weight gain.

Another pathway that appears to intersect with the cholinergicanti-inflammatory pathway, and one that is directly relevant to a keycomponent of the metabolic syndrome, involves the protein tyrosinephosphatase (PTP) PTP1B. Specifically, PTP1B has been shown to act as anegative regulator of insulin signaling. Overexpression of PTP1B impairsinsulin signals, whereas loss of PTP1B is associated with increasedsensitivity to insulin. PTP1B binds to and catalyzes thedephosphorylation of the insulin receptor and many of the effects ofPTP1B on insulin signaling can be explained on the basis of thisinteraction. Studies have shown that deletion of the phosphotyrosinephosphatase PTP1B improves insulin signaling in mouse models of obesityand PTP1B antagonists have been used pharmacologically to improveglucose tolerance. More importantly, PTP1B has also been reported todephosphorylate JAK2, suggesting that there is cross-talk between the α7nAChR-linked anti-inflammatory pathway and insulin regulation. SincePTP1B regulates body weight, adiposity and leptin action, α7 nAChRs mayplay a critical role in regulating numerous aspects of the metabolicsyndrome.

The specific pharmacological responses observed may vary according toand depending on the particular active compound selected or whetherthere are present pharmaceutical carriers, as well as the type offormulation and mode of administration employed, and such expectedvariations or differences in the results are contemplated in accordancewith practice of the present invention.

Although specific embodiments of the present invention are hereinillustrated and described in detail, the invention is not limitedthereto. The above detailed descriptions are provided as exemplary ofthe present invention and should not be construed as constituting anylimitation of the invention. Modifications will be obvious to thoseskilled in the art, and all modifications that do not depart from thespirit of the invention are intended to be included with the scope ofthe appended claims.

1. A method for treating or preventing metabolic disorders comprisingthe administration of a selective α7 nAChR agonist.
 2. A method fortreating or preventing drug-induced central nervous system disorderscomprising the administration of a selective α7 nAChR agonist.
 3. Themethod of claim 1, wherein the α7 nAChR agonist is Compound A, CompoundB, Compound C, or a pharmaceutically acceptable salt thereof.
 4. Themethod of claim 1, wherein the α7 nAChR agonist is Compound C or apharmaceutically acceptable salt thereof.
 5. The method of claim 1,wherein the metabolic disorder is one or more of type I diabetesmellitus, type II diabetes mellitus, metabolic syndrome,atherosclerosis, obesity, and hyperglycemia.
 6. The method of claim 5,wherein the hyperglycemia is a result of statin therapy.
 7. The methodof claim 2, wherein the drug-induced central nervous system disorder isa result of statin therapy.
 8. A method for treating or preventing ametabolic disorder comprising the administration of

or a pharmaceutically acceptable salt thereof.
 9. The method of claim 8,wherein the metabolic disorder is one or more of type I diabetesmellitus, type II diabetes mellitus, metabolic syndrome,atherosclerosis, obesity, and hyperglycemia.
 10. The method of claim 9,wherein a daily dose is from about 0.001 mg/kg to about 3.0 mg/kg.11-30. (canceled)
 31. The method of claim 2, wherein the α7 nAChRagonist is Compound A, Compound B, Compound C, or a pharmaceuticallyacceptable salt thereof.
 32. The method of claim 2, wherein the α7 nAChRagonist is Compound C or a pharmaceutically acceptable salt thereof. 33.A compound(2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide

or a pharmaceutically acceptable salt thereof.